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Burst discharges in the immature brain may contribute to its enhanced seizure susceptibility. The cellular mechanisms underlying burst discharges in the CA1 area of the immature versus adult hippocampus were investigated with simultaneous whole-cell and field-potential recordings. When GABA A receptors were blocked pharmacologically, bursts in CA1 were either graded or all-or-none (or mixed) as a function of electrical stimulation intensity. Most CA1 minislices from immature rats displayed all-or-none or mixed bursts, whereas the slices from adult rats predominantly elicited graded bursts. The frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) were greater in CA1 pyramidal cells from the immature than the adult slices. The developmental differences in CA1 bursting were also detected in slices adjusted for maturational changes in brain volume (i.e., 350 µm thick for immature vs. 450 µm thick for adult rats). Neither N -methyl-d-aspartate (NMDA) nor group I metabotropic glutamate (mGlu1) receptor antagonists blocked the network-driven bursts in immature CA1, but an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker abolished them. Robust excitatory postsynaptic potentials (EPSPs) occurred after bursts in some immature CA1 slices (23%) but never in slices from the adult. The input-output (amount of current injected vs. number of action potentials generated) relationship was markedly greater in CA1 pyramidal cells in the immature compared with the adult hippocampus. These data suggest that the CA1 area of the immature brain is capable of generating network-driven bursts, which declines in adult rats. The increased propensity of burst generation in immature CA1 appears to involve a greater AMPA receptor-mediated synaptic network and an increased intrinsic spike-generating ability. NEW & NOTEWORTHY Burst discharges in the developing brain can provide valuable insights into epileptogenesis. We show that the immature hippocampal CA1 area is capable of generating all-or-none (i.e., network) bursts, which transitions to graded (i.e., nonnetwork) bursts in the mature brain via both synaptic and intrinsic mechanisms. Our results provide new clues to help understand possible mechanisms that may be shared in the immature and epileptic brain and how the normal brain becomes seizure prone (i.e., epileptogenesis).

Biochemical mechanisms are temperature dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here, we report on the relationship between various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate, and duration correlated with temperature dynamics. By focal manipulation of the brain temperature in the hippocampal CA1 region, we show that ripple frequency can be increased and decreased by local heating and cooling, respectively. Changes of other parameters, such as the rate of sharp wave-ripple complex (SPW-R) and ripple duration were not consistently affected. Our findings suggest that brain temperature in the CA1 region plays a leading role in affecting ripple frequency, whereas other parameters of SPW-Rs may be determined by mechanisms upstream from the CA1 region. These findings illustrate that physiological variations of brain temperature exert important effects on hippocampal circuit operations. NEW & NOTEWORTHY During physiological conditions, brain temperature fluctuates approximately 3°C between sleep and active waking. Here, we show that features of hippocampal ripples, including the rate of occurrence, peak frequency, and duration are correlated with brain temperature variations. Focal bidirectional manipulation of temperature in the hippocampal CA1 region in awake rodents show that ripple frequency can be altered in the direction expected from the correlational observations, implying that temperature plays a significant role.

Thirst is an important interoceptive response and drives water consumption. The hippocampus actively modulates food intake and energy metabolism, but direct evidence for the exact role of the hippocampus in modulating drinking behaviors is lacking. We observed decreased number of c-Fos-positive neurons in the ventral hippocampal CA1 (vCA1) after water restriction or hypertonic saline injection in rats. Suppressed vCA1 neuronal activities under the hypertonic state were further confirmed with in vivo electrophysiological recording, and the level of suppression paralleled both the duration and the total amount of water consumption. Chemogenetic inhibition of vCA1 pyramidal neurons increased water consumption in rats injected with both normal and hypertonic saline. These findings suggest that suppression of vCA1 pyramidal neuronal activities enhances water intake.

The nonsinusoidal waveform is emerging as an important feature of neuronal oscillations. However, the role of single-cycle shape dynamics in rapidly unfolding brain activity remains unclear. Here, we develop an analytical framework that isolates oscillatory signals from time series using masked empirical mode decomposition to quantify dynamical changes in the shape of individual cycles (along with amplitude, frequency, and phase) with instantaneous frequency. We show how phase-alignment, a process of projecting cycles into a regularly sampled phase grid space, makes it possible to compare cycles of different durations and shapes. "Normalized shapes" can then be constructed with high temporal detail while accounting for differences in both duration and amplitude. We find that the instantaneous frequency tracks nonsinusoidal shapes in both simulated and real data. Notably, in local field potential recordings of mouse hippocampal CA1, we find that theta oscillations have a stereotyped slow-descending slope in the cycle-wise average yet exhibit high variability on a cycle-by-cycle basis. We show how principal component analysis allows identification of motifs of theta cycle waveform that have distinct associations to cycle amplitude, cycle duration, and animal movement speed. By allowing investigation into oscillation shape at high temporal resolution, this analytical framework will open new lines of inquiry into how neuronal oscillations support moment-by-moment information processing and integration in brain networks. NEW & NOTEWORTHY We propose a novel analysis approach quantifying nonsinusoidal waveform shape. The approach isolates oscillations with empirical mode decomposition before waveform shape is quantified using phase-aligned instantaneous frequency. This characterizes the full shape profile of individual cycles while accounting for between-cycle differences in duration, amplitude, and timing. We validated in simulations before applying to identify a range of data-driven nonsinusoidal shape motifs in hippocampal theta oscillations.

The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells-an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons-during simulated θ rhythms. We use previously developed multicompartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs during in vitro and in vivo scenarios contribute to θ. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via postinhibitory rebound mechanisms, and contribute to θ frequency spike resonance during simulated in vivo scenarios. To elicit recruitment similar to in vitro experiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Using in vivo virtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at θ frequencies. Furthermore, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways. NEW & NOTEWORTHY How information is processed across different brain structures is an important question that relates to the different functions that the brain performs. Using modeling and theoretical analyses, we show that an inhibitory cell type that only inhibits other inhibitory cells can broaden the window for disinhibition of excitatory cells, manage input pathway switching, and modulate inhibitory cell spiking. This work contributes to the knowledge of how coordination between sensory and memory consolidation information can be attained.

Potassium channels play an important role regulating transmembrane electrical activity in essentially all cell types. We were especially interested in those that determine the intrinsic electrical properties of mammalian central neurons. Over 30 different potassium channels have been molecularly identified in brain neurons, but there often is not a clear distinction between molecular structure and the function of a particular channel in the cell. Using patch-clamp methods to search for single potassium channels in excised inside-out (ISO) somatic patches with symmetrical potassium, we found that nearly all patches contained non-voltage-inactivating channels with a single-channel conductance of 100-200 pS. This conductance range is consistent with the family of sodium-activated potassium channels (Slo2.1, Slo2.2, or collectively, K Na ). The activity of these channels was positively correlated with a low cytoplasmic Na + concentration (2-20 mM). Cell-attached recordings from intact neurons, however, showed little or no activity of this K + channel. Attempts to increase channel activity by increasing intracellular sodium concentration ([Na + ] i ) with bursts of action potentials or direct perfusion of Na + through a whole cell pipette had little effect on K Na channel activity. Furthermore, excised outside-out (OSO) patches across a range of intracellular [Na + ] showed less channel activity than we had seen with excised ISO patches. Blocking the Na + /K + pump with ouabain increased the activity of the K Na channels in excised OSO patches to levels comparable with ISO-excised patches. Our results suggest that despite their apparent high levels of expression, the activity of somatic K Na channels is tightly regulated by the activity of the Na + /K + pump. NEW & NOTEWORTHY We studied K Na channels in mouse hippocampal CA1 neurons. Excised inside-out patches showed the channels to be prevalent and active in most patches in the presence of Na + . Cell-attached recordings from intact neurons, however, showed little channel activity. Increasing cytoplasmic sodium in intact cells showed a small effect on channel activity compared with that seen in inside-out excised patches. Blockade of the Na + /K + pump with ouabain, however, restored the activity of the channels to that seen in inside-out patches.

Cell firing has been reported to variably upregulate or downregulate subsequently induced long-term potentiation (LTP). The aim of this study was to elucidate the parameters critical to driving each direction of the metaplasticity effect. The main focus was on the commonly used θ-burst stimulation (TBS) and high-frequency stimulation (HFS) protocols that are known to trigger distinct intracellular signaling cascades. To study action potential (AP)-induced metaplasticity, we used intracellular recordings from CA1 pyramidal cells of rat hippocampal slices. Somatic current injections were used to induce θ-burst firing (TBF) or high-frequency firing (HFF) for priming purposes, whereas LTP was induced 15   min later via TBS of Schaffer collaterals in stratum radiatum. TBS-LTP was inhibited by both priming protocols. Conversely, HFS-LTP was facilitated by HFF priming but not affected by TBF priming. Interestingly, both priming protocols reduced AP firing during TBS-LTP induction, and this effect correlated with the reduction of TBS-LTP. However, LTP was not rescued by restoring AP firing with somatic current injections during the TBS. Analysis of intrinsic properties revealed few changes, apart from a priming-induced increase in the medium afterhyperpolarization (HFF priming) and a decrease in the EPSP amplitude/slope ratio (TBF priming), which could in principle contribute to the inhibition of TBS-LTP by reducing depolarization and associated Ca 2+ influx following synaptic activity or AP backpropagation. Overall, these data indicate that the more physiological TBS protocol for inducing LTP is particularly susceptible to homeostatic feedback inhibition by prior bouts of postsynaptic cell firing. NEW & NOTEWORTHY The induction of LTP in the hippocampus was bidirectionally regulated by prior postsynaptic cell firing, with θ-burst stimulation-induced LTP being consistently impaired by prior spiking, whereas high-frequency stimulation-induced LTP was either not changed or facilitated. Reductions in cell firing during LTP induction did not explain the LTP impairment. Overall, different patterns of postsynaptic firing induce distinct intracellular changes that can increase or decrease LTP depending on the induction protocol.

The death-associated protein kinase 1 (DAPK1) has recently been shown to have a physiological function in long-term depression (LTD) of glutamatergic synapses: acute inhibition of DAPK1 blocked the LTD that is normally seen at the hippocampal CA1 synapse in young mice, and a pharmacogenetic combination approach showed that this specifically required DAPK1-mediated suppression of postsynaptic Ca 2+ /calmodulin-dependent protein kinase II binding to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B during LTD stimuli. Surprisingly, we found here that genetic deletion of DAPK1 (in DAPK1 -/- mice) did not reduce LTD. Paired pulse facilitation experiments indicated a presynaptic compensation mechanism: in contrast to wild-type mice, LTD stimuli in DAPK1 -/- mice decreased presynaptic release probability. Basal synaptic strength was normal in young DAPK1 -/- mice, but basal glutamate release probability was reduced, an effect that normalized with maturation. NEW & NOTEWORTHY Young death-associated protein kinase 1 (DAPK1) knockout mice have reduced basal glutamate release probability, an effect that normalized with maturation. This provided a compensatory mechanism that may have prevented a reduction of long-term depression in the young DAPK1 knockout mice.

The Na + -K + -ATPase (Na + -K + pump) is essential for setting resting membrane potential and restoring transmembrane Na + and K + gradients after neuronal firing, yet its roles in developing neurons are not well understood. This study examined the contribution of the Na + -K + pump to resting membrane potential and membrane excitability of developing CA1 and CA3 neurons and its role in maintaining synchronous network bursting. Experiments were conducted in postnatal day (P)9 to P13 rat hippocampal slices using whole cell patch-clamp and extracellular field-potential recordings. Blockade of the Na + -K + pump with strophanthidin caused marked depolarization (23.1   mV) in CA3 neurons but only a modest depolarization (3.3   mV) in CA1 neurons. Regarding other membrane properties, strophanthidin differentially altered the voltage-current responses, input resistance, action-potential threshold and amplitude, rheobase, and input-output relationship in CA3 vs. CA1 neurons. At the network level, strophanthidin stopped synchronous epileptiform bursting in CA3 induced by 0 Mg 2+ and 4-aminopyridine. Furthermore, dual whole cell recordings revealed that strophanthidin disrupted the synchrony of CA3 neuronal firing. Finally, strophanthidin reduced spontaneous excitatory postsynaptic current (sEPSC) bursts (i.e., synchronous transmitter release) and transformed them into individual sEPSC events (i.e., nonsynchronous transmitter release). These data suggest that the Na + -K + pump plays a more profound role in membrane excitability in developing CA3 neurons than in CA1 neurons and that the pump is essential for the maintenance of synchronous network bursting in CA3. Compromised Na + -K + pump function leads to cessation of ongoing synchronous network activity, by desynchronizing neuronal firing and neurotransmitter release in the CA3 synaptic network. These findings have implications for the regulation of network excitability and seizure generation in the developing brain. NEW & NOTEWORTHY Despite the extensive literature showing the importance of the Na + -K + pump in various neuronal functions, its roles in the developing brain are not well understood. This study reveals that the Na + -K + pump differentially regulates the excitability of CA3 and CA1 neurons in the developing hippocampus, and the pump activity is crucial for maintaining network activity. Compromised Na + -K + pump activity desynchronizes neuronal firing and transmitter release, leading to cessation of ongoing epileptiform network bursting.

Neural oscillations are routinely analyzed using methods that measure activity in fixed frequency bands (e.g., alpha, 8-12 Hz), although the frequency of neural signals varies within and across individuals based on numerous factors including neuroanatomy, behavioral demands, and species. Furthermore, band-limited activity is an often assumed, typically unmeasured model of neural activity, and band definitions vary considerably across studies. Together, these factors mask individual differences and can lead to noisy spectral estimates and interpretational problems when linking electrophysiology to behavior. We developed the Oscillatory ReConstruction Algorithm ("ORCA"), an unsupervised method to measure the spectral characteristics of neural signals in adaptively identified bands, which incorporates two new methods for frequency band identification. ORCA uses the instantaneous amplitude, phase, and frequency of activity in each band to reconstruct the signal and directly quantify spectral decomposition performance using each of four different models. To reduce researcher bias, ORCA provides spectral estimates derived from the best model and requires minimal hyperparameterization. Analyzing human scalp EEG data during eyes-open and eyes-closed "resting" conditions, we first identify variability in the frequency content of neural signals across subjects and electrodes. We demonstrate that ORCA significantly improves spectral decomposition compared with conventional methods and captures the well-known increase in low-frequency activity during eye closure in electrode- and subject-specific frequency bands. We further illustrate the utility of our method in rodent CA1 recordings. ORCA is a novel analytic tool that allows researchers to investigate how nonstationary neural oscillations vary across behaviors, brain regions, individuals, and species. NEW & NOTEWORTHY Neural oscillations show substantial variability within and across individuals and brain regions, yet most existing studies analyze oscillations using canonical, fixed-frequency bands. Thus, there is an ongoing need for tools that capture oscillatory variability in neural signals. Toward this end, Oscillatory ReConstruction Algorithm is a novel and adaptive analytic tool that allows researchers to measure neural oscillations with more precision and less researcher bias.

Significant evidence has accumulated to support the hypothesis that hippocampal region CA1 operates as an associative mismatch detector (e.g., Hasselmo ME, Schnell E, Barkai E. J Neurosci 15: 5249-5262, 1995; Duncan K, Curtis C, Davachi L. J Neurosci 29: 131-139, 2009; Kumaran D, Maguire EA. J Neurosci 27: 8517-8524, 2007; Lisman JE, Grace AA. Neuron 46: 703-713, 2005; Lisman JE, Otmakhova NA. Hippocampus 11: 551-568 2001; Lörincz A, Buzsáki G. Ann N Y Acad Sci 911: 83-111, 2000; Meeter M, Murre JMJ, Talamini LM. Hippocampus 14: 722-741, 2004; Schiffer AM, Ahlheim C, Wurm MF, Schubotz RI. PLoS One 7: e36445, 2012; Vinogradova OS. Hippocampus 11: 578-598 2001). CA1 compares predictive synaptic signals from CA3 with synaptic signals from EC3, which reflect actual sensory inputs. The new CA1 pyramidal model presented here shows that the distal-proximal segregation of synaptic inputs from EC3 versus CA3, along with other biophysical features, enable such pyramids to serve as comparators that switch output encoding from a brief burst, for a match, to prolonged tonic spiking, for a mismatch. By including often-overlooked features of CA1 pyramidal neurons, this new model allows simulation of pharmacological effects that can eliminate either the match (phasic mode) response or the mismatch (tonic mode) response. These simulations reveal that dysfunctions can arise from either too much or too little ACh stimulation of the muscarinic receptors that control KCNQ channels. Additionally, a dysfunction caused by administration of an N -methyl-d-aspartate antagonist could be rescued by simultaneous administration of a KCNQ channel agonist, such as retigabine. NEW & NOTEWORTHY Hippocampal region CA1 operates as an associative mismatch detector, comparing predictive signals from CA3 with signals from EC3 reflecting sensory inputs. This new CA1 pyramidal model shows that biophysical features enable these comparators to switch output between brief bursts for matches and tonic spiking for mismatches. This suggests that cognitive learning models (e.g., predictive coding) may require much less match/mismatch circuitry than commonly assumed. Additional simulations illuminate deficits seen in psychiatric disorders and drug-induced states.

Hippocampus forms neural representations of real-life events including multimodal information of spatial and temporal context. These representations, i.e., organized sequences of neuronal firing, are repeated during following rest and sleep, especially when so-called sharp-wave ripples (SPW-Rs) characterize hippocampal local field potentials. This SPW-R -related replay is thought to underlie memory consolidation. Here, we set out to explore how hippocampal CA1 pyramidal cells respond to the conditioned stimulus during trace eyeblink conditioning and how these responses manifest during SPW-Rs in awake adult female New Zealand White rabbits. Based on reports in rodents, we expected SPW-Rs to take place in bursts, possibly according to a slow endogenous rhythm. In awake rabbits, half of all SPW-Rs took place in bursts, but no endogenous slow rhythm appeared. Conditioning trials suppressed SPW-Rs while increasing theta for a period of several seconds. As expected based on previous findings, only a quarter of the putative CA1 pyramidal cells increased firing in response to the conditioned stimulus. Compared with other cells, rate-increasing cells were more active during spontaneous epochs of hippocampal theta while response profile during conditioning did not affect firing during SPW-Rs. Taken together, CA1 pyramidal cell firing during SPW-Rs is not limited to cells that fired during the preceding experience. Furthermore, the importance of possible reactivations taking place during theta epochs on memory consolidation warrants further investigation. NEW & NOTEWORTHY We studied hippocampal sharp-wave ripples and theta and CA1 pyramidal cell activity during trace eyeblink conditioning in rabbits. Conditioning trials suppressed ripples while increasing theta for a period of several seconds. A quarter of the cells increased firing in response to the conditioned stimulus and fired extensively during endogenous theta as well as ripples. The role of endogenous theta epochs in off-line memory consolidation should be studied further.

The population activity of CA1 pyramidal neurons (PNs) segregates along anatomical axes with different behaviors, suggesting that CA1 PNs are functionally subspecialized based on somatic location. In dorsal CA1, spatial encoding is biased toward CA2 (CA1c) and in deep layers of the radial axis. In contrast, nonspatial coding peaks toward subiculum (CA1a) and in superficial layers. While preferential innervation by spatial vs. nonspatial input from entorhinal cortex (EC) may contribute to this specialization, it cannot fully explain the range of in vivo responses. Differences in intrinsic properties thus may play a critical role in modulating such synaptic input differences. In this study we examined the postsynaptic integrative properties of dorsal CA1 PNs in six subpopulations along the transverse (CA1c, CA1b, CA1a) and radial (deep, superficial) axes. Our results suggest that active and passive properties of deep and superficial neurons evolve over the transverse axis to promote the functional specialization of CA1c vs. CA1a as dictated by their cortical input. We also find that CA1b is not merely an intermediate mix of its neighbors, but uniquely balances low excitability with superior input integration of its mixed input, as may be required for its proposed role in sequence encoding. Thus synaptic input and intrinsic properties combine to functionally compartmentalize CA1 processing into at least three transverse axis regions defined by the processing schemes of their composite radial axis subpopulations. NEW & NOTEWORTHY There is increasing interest in CA1 pyramidal neuron heterogeneity and the functional relevance of this diversity. We find that active and passive properties evolve over the transverse and radial axes in dorsal CA1 to promote the functional specialization of CA1c and CA1a for spatial and nonspatial memory, respectively. Furthermore, CA1b is not a mean of its neighbors, but features low excitability and superior integrative capabilities, relevant to its role in nonspatial sequence encoding.

Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to the hippocampus, respectively. Whether the distinct inputs are integrated as one cognitive map by hippocampal neurons to represent location and the objects therein, or whether they remain as parallel outputs, to be integrated in a downstream region, remains unclear. Principal, or complex spike bursting, neurons of hippocampus exhibit location-specific firing, and it is likely that the activity of "place cells" supports spatial memory/navigation in rodents. Consistent with cognitive map theory, the activity of CA1 hippocampal neurons is also critical for nonspatial memory, such as object recognition. However, the degree to which CA1 neuronal activity represents the associations of object-context or object-in-place memory is not well understood. Here, the contributions of mouse CA1 neuronal activity to object recognition memory and the emergence of object-place conjunctive representations were tested using in vivo recordings and functional inactivation. Independent of arena configuration, CA1 place fields were stable throughout testing and object-place representations were not identified in CA1, although the number of fields per cell increased during object sessions, and few object-related firing CA1 neurons (nonplace) were recorded. The results of the inactivation studies confirmed the significant contribution of CA1 neuronal activity to object recognition memory when a delay of 20 min, but not 5 min, was imposed between encoding and retrieval. Together, our results confirm the delay-dependent contribution of the CA1 region to object memory and suggest that object information is processed in parallel with the ongoing spatial mapping function that is a hallmark of hippocampal memory. NEW & NOTEWORTHY We developed variations of the object recognition task to examine the contribution of mouse CA1 neuronal activity to object memory and the degree to which object-context conjunctive representations are formed during object training. Our results indicate that, within the CA1 region, object information is processed in a parallel but delay-dependent manner, with ongoing spatial mapping.

Our brains must maintain a representation of the world over a period of time much longer than the typical lifetime of the biological components producing that representation. For example, recent research suggests that dendritic spines in the adult mouse hippocampus are transient with an average lifetime of ~10 days. If this is true, and if turnover is equally likely for all spines, ~95% of excitatory synapses onto a particular neuron will turn over within 30 days; however, a neuron's receptive field can be relatively stable over this period. Here, we use computational modeling to ask how memories can persist in neural circuits such as the hippocampus and visual cortex in the face of synapse turnover. We demonstrate that Hebbian plasticity during replay of presynaptic activity patterns can integrate newly formed synapses into pre-existing memories. Furthermore, we find that Hebbian plasticity during replay is sufficient to stabilize the receptive fields of hippocampal place cells in a model of the grid-cell-to-place-cell transformation in CA1 and of orientation-selective cells in a model of the center-surround-to-simple-cell transformation in V1. Together, these data suggest that a simple plasticity rule, correlative Hebbian plasticity of synaptic strengths, is sufficient to preserve neural representations in the face of synapse turnover, even in the absence of activity-dependent structural plasticity. NEW & NOTEWORTHY Recent research suggests that synapses turn over rapidly in some brain structures; however, memories seem to persist for much longer. We show that Hebbian plasticity of synaptic strengths during reactivation events can preserve memory in computational models of hippocampal and cortical networks despite turnover of all synapses. Our results suggest that memory can be stored in the correlation structure of a network undergoing rapid synaptic remodeling.

Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialyzed cells. Suppression of both the medium and slow AHPs was antagonized by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β 3 -adrenergic receptor agonists, BRL37344 and SR58611A. The medium AHP was mediated by activation of small-conductance calcium-activated K + channels and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pretreating cells with the H-channel blocker ZD7288. These data suggest that activation of β 3 -adrenergic receptors inhibits H channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilizing a pathway that is independent of a rise in intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity and thereby neuronal excitability. NEW & NOTEWORTHY The noradrenergic input into the hippocampus is involved in modulating long-term synaptic plasticity and is implicated in learning and memory. We demonstrate that activation of functional β 3 -adrenergic receptors suppresses the medium afterhyperpolarization in hippocampal pyramidal neurons. This finding provides an additional mechanism to increase action potential firing frequency, where neuronal excitability is likely to be crucial in cognition and memory.

Specific memory processes and neurological disorders can be ascribed to different dorsoventral regions of the hippocampus. Recently, differences in the anatomical and physiological properties between dorsal and ventral hippocampal CA1 neurons were described for both the rat and mouse hippocampus and have greatly contributed to our understanding of these processes. While differences in the subthreshold properties were similar between rat and mouse neurons, differences in action potential output between dorsal and ventral neurons were strikingly less divergent in mouse compared with rat CA1 neurons. Here, we investigate the mechanism underlying the lack of difference in action potential firing between dorsal and ventral CA1 pyramidal neurons in mouse hippocampus. Consistent with rat, we found that ventral CA1 neurons had a more depolarized resting membrane potential and higher input resistance than dorsal CA1 neurons in the mouse hippocampus. Despite these differences, action potential output in response to current injection was not significantly different. We found that ventral neurons have a more depolarized action potential threshold compared with dorsal neurons and that threshold in ventral neurons was more sensitive to block of K V 1 channels compared with dorsal neurons. Outside-out voltage-clamp recordings found that slowly inactivating K + currents were larger in ventral CA1 neurons. These results suggest that, despite differences in subthreshold properties between dorsal and ventral CA1 neurons, action potential output is normalized by the differential functional expression of D-type K + channels. NEW & NOTEWORTHY Understanding differences in neurons within a brain region is integral in the reliable interpretation of comparative studies. Our findings identify a novel mechanism by which D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of mouse hippocampus despite differences in subthreshold intrinsic properties. Action potential threshold in ventral neurons is influenced by a greater functional expression of D-type potassium channels resulting in a depolarized action potential threshold compared with dorsal hippocampus.

Although the activation of extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors has been implicated in neurodegenerative diseases, such as Alzheimer's and Huntington's disease, their physiological function remains unknown. In this study, we found that extrasynaptic GluN2B receptors play a homeostatic role by antagonizing long-term potentiation (LTP) induction under conditions of prolonged synaptic stimulation. In particular, we have previously found that brief theta-pulse stimulation (5 Hz for 30 s) triggers robust LTP, whereas longer stimulation times (5 Hz for 3 min) have no effect on basal synaptic transmission in the hippocampal CA1 region. Here, we show that prolonged stimulation blocked LTP by activating extrasynaptic GluN2B receptors via glutamate spillover. In addition, we found that this homeostatic mechanism was absent in slices from the SAP102 knockout, providing evidence for a functional coupling between extrasynaptic GluN2B and the SAP102 scaffold protein. In conclusion, we uncovered a rapid homeostatic mechanism that antagonizes LTP induction via the activation of extrasynaptic GluN2B-containing NMDA receptors. NEW & NOTEWORTHY Although long-term potentiation (LTP) is an attractive model for memory storage, it tends to destabilize neuronal circuits because it drives synapses toward a maximum value. Unless opposed by homeostatic mechanisms operating through negative feedback rules, cumulative LTP could render synapses unable to encode additional information. In this study, we uncovered a rapid homeostatic mechanism that antagonizes LTP induction under conditions of prolonged synaptic stimulation via the activation of an extrasynaptic GluN2B-SAP102 complex.

The postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD/DLG-MAGUK) family of proteins scaffold α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complexes to the postsynaptic compartment and are postulated to orchestrate activity-dependent modulation of synaptic AMPAR functions. SAP102 is a key member of this family, present from early development, before PSD-95 and PSD-93, and throughout life. Here we investigate the role of SAP102 in synaptic transmission using a cell-restricted molecular replacement strategy, where SAP102 is expressed against the background of acute knockdown of endogenous PSD-95. We show that SAP102 rescues the decrease of AMPAR-mediated evoked excitatory postsynaptic currents (AMPAR eEPSCs) and AMPAR miniature EPSC (AMPAR mEPSC) frequency caused by acute knockdown of PSD-95. Further analysis of the mini events revealed that PSD-95-to-SAP102 replacement but not direct manipulation of PSD-95 increases the AMPAR mEPSC decay time. SAP102-mediated rescue of AMPAR eEPSCs requires AMPAR auxiliary subunit cornichon-2, whereas cornichon-2 knockdown did not affect PSD-95-mediated regulation of AMPAR eEPSC. Combining these observations, our data elucidate that PSD-95 and SAP102 differentially influence basic synaptic properties and synaptic current kinetics potentially via different AMPAR auxiliary subunits. NEW & NOTEWORTHY Synaptic scaffold proteins postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD-MAGUKs) regulate synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function. However, the functional diversity among different PSD-MAGUKs remains to be categorized. We show that distinct from PSD-95, SAP102 increase the AMPAR synaptic current decay time, and the effect of SAP102 on synaptic AMPAR function requires the AMPAR auxiliary subunit cornichon-2. Our data suggest that PSD-MAGUKs target and modulate different AMPAR complexes to exert specific experience-dependent modification of the excitatory circuit.

Cardiac cycle phase is known to modulate processing of simple sensory information. This effect of the heartbeat on brain function is likely exerted via baroreceptors, the neurons sensitive for changes in blood pressure. From baroreceptors, the signal is conveyed all the way to the forebrain and the medial prefrontal cortex. In the two experiments reported, we examined whether learning, as a more complex form of cognition, can be modulated by the cardiac cycle phase. Human participants ( experiment 1) and rabbits ( experiment 2) were trained in trace eyeblink conditioning while neural activity was recorded. The conditioned stimulus was presented contingently with either the systolic or diastolic phase of the cycle. The tone used as the conditioned stimulus evoked amplified responses in both humans (electroencephalogram from "vertex," Cz) and rabbits (hippocampal CA1 local field potential) when its onset was timed at systole. In humans, the cardiac cycle phase did not affect learning, but rabbits trained at diastole learned significantly better than those trained at a random phase of the cardiac cycle. In summary, our results suggest that neural processing of external stimuli and also learning can be affected by targeting stimuli on the basis of cardiac cycle phase. These findings might be useful in applications aimed at maximizing or minimizing the effects of external stimulation. NEW & NOTEWORTHY It has been shown that rapid changes in bodily states modulate neural processing of external stimulus in brain. In this study, we show that modulation of neural processing of external stimulus and learning about it depends on the phase of the cardiac cycle. This is a novel finding that can be applied to optimize associative learning.

Although long thought to simply be a source of synaptic noise, spontaneous, action potential-independent release of neurotransmitter from presynaptic terminals has multiple roles in synaptic function. We explored whether and to what extent the two predominantly proposed mechanisms for explaining spontaneous release, stochastic activation of voltage-gated Ca 2+ channels (VGCCs) or activation of Ca 2+ -sensing receptors (CaSRs) by extracellular Ca 2+ , played a role in the sensitivity of spontaneous release to the level of extracellular Ca 2+ concentration at excitatory synapses at CA1 pyramidal cells of the adult male mouse hippocampus. Blocking VGCCs with Cd 2+ had no effect on spontaneous release, ruling out stochastic activation of VGCCs. Although divalent cation agonists of CaSRs, Co 2+ and Mg 2+ , dramatically enhanced miniature excitatory postsynaptic current (mEPSC) frequency, potent positive and negative allosteric modulators of CaSRs had no effect. Moreover, immunoblot analysis of hippocampal lysates failed to detect CaSR expression, ruling out the CaSR. Instead, the increase in mEPSC frequency induced by Co 2+ and Mg 2+ was mimicked by lowering postsynaptic Ca 2+ levels with BAPTA. Together, our results suggest that a reduction in intracellular Ca 2+ may trigger a homeostatic-like compensatory response that upregulates spontaneous transmission at excitatory synapses onto CA1 pyramidal cells in the adult hippocampus. NEW & NOTEWORTHY We show that the predominant theories for explaining the regulation of spontaneous, action potential-independent synaptic release do not explain the sensitivity of this type of synaptic transmission to external Ca 2+ concentration at excitatory synapses onto hippocampal CA1 pyramidal cells. In addition, our data indicate that intracellular Ca 2+ levels in CA1 pyramidal cells regulate spontaneous release, suggesting that excitatory synapses onto CA1 pyramidal cells may express a novel, rapid form of homeostatic plasticity.

CA1 place cells become more anticipatory with experience, an effect thought to be caused by NMDA receptor-dependent plasticity in the CA3-CA1 network. Theta (~5-12 Hz), slow gamma (~25-50 Hz), and fast gamma (~50-100 Hz) rhythms are thought to route spatial information in the hippocampal formation and to coordinate place cell ensembles. Yet, it is unknown whether these rhythms exhibit experience-dependent changes concurrent with those observed in place cells. Slow gamma rhythms are thought to indicate inputs from CA3 to CA1, and such inputs are thought to be strengthened with experience. Thus, we hypothesized that slow gamma rhythms would become more evident with experience. We tested this hypothesis using mice freely traversing a familiar circular track for three 10-min sessions per day. We found that slow gamma amplitude was reduced in the early minutes of the first session of each day, even though both theta and fast gamma amplitudes were elevated during this same period. However, in the first minutes of the second and third sessions of each day, all three rhythms were elevated. Interestingly, theta was elevated to a greater degree in the first minutes of the first session than in the first minutes of later sessions. Additionally, all three rhythms were strongly influenced by running speed in dynamic ways, with the influence of running speed on theta and slow gamma changing over time within and across sessions. These results raise the possibility that experience-dependent changes in hippocampal rhythms relate to changes in place cell activity that emerge with experience. NEW & NOTEWORTHY We show that CA1 theta, slow gamma, and fast gamma rhythms exhibit characteristic changes over time within sessions in familiar environments. These effects in familiar environments evolve across repeated sessions.

The ability to distill specific frequencies from complex spatiotemporal patterns of afferent inputs is a pivotal functional requirement for neurons residing in networks receiving frequency-multiplexed inputs. Although the expression of theta-frequency subthreshold resonance is established in hippocampal pyramidal neurons, it is not known if their spike initiation dynamics manifest spectral selectivity, or if their intrinsic properties are tuned to process gamma-frequency inputs. Here, we measured the spike-triggered average (STA) of rat hippocampal pyramidal neurons through electrophysiological recordings and quantified spectral selectivity in their spike initiation dynamics and their coincidence detection window (CDW). Our results revealed strong theta-frequency selectivity in the STA, which was also endowed with gamma-range CDW, with prominent neuron-to-neuron variability that manifested distinct pairwise dissociations and correlations with different intrinsic measurements. Furthermore, we demonstrate that the STA and its measurements substantially adapted to the state of the neuron defined by its membrane potential and to the statistics of its afferent inputs. Finally, we tested the effect of pharmacologically blocking the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels on the STA and found that the STA characteristic frequency reduced significantly to the delta-frequency band after HCN channel blockade. This delta-frequency selectivity in the STA emerged in the absence of subthreshold resonance, which was abolished by HCN channel blockade, thereby confirming computational predictions on the dissociation between these two forms of spectral selectivity. Our results expand the roles of HCN channels to theta-frequency selectivity in the spike initiation dynamics, apart from underscoring the critical role of interactions among different ion channels in regulating neuronal physiology. NEW & NOTEWORTHY We had previously predicted, using computational analyses, that the spike-triggered average (STA) of hippocampal neurons would exhibit theta-frequency (4-10 Hz) spectral selectivity and would manifest coincidence detection capabilities for inputs in the gamma-frequency band (25-150 Hz). Here, we confirmed these predictions through direct electrophysiological recordings of STA from rat CA1 pyramidal neurons and demonstrate that blocking HCN channels reduces the frequency of STA spectral selectivity to the delta-frequency range (0.5-4 Hz)., (Copyright © 2017 the American Physiological Society.)

Seconds-scale network states, affecting many neurons within a network, modulate neural activity by complementing fast integration of neuron-specific inputs that arrive in the milliseconds before spiking. Nonrhythmic subthreshold dynamics at intermediate timescales, however, are less well characterized. We found, using automated whole cell patch clamping in vivo, that spikes recorded in CA1 and barrel cortex in awake mice are often preceded not only by monotonic voltage rises lasting milliseconds but also by more gradual (lasting tens to hundreds of milliseconds) depolarizations. The latter exert a gating function on spiking, in a fashion that depends on the gradual rise duration: the probability of spiking was higher for longer gradual rises, even when controlled for the amplitude of the gradual rises. Barrel cortex double-autopatch recordings show that gradual rises are shared across some, but not all, neurons. The gradual rises may represent a new kind of state, intermediate both in timescale and in proportion of neurons participating, which gates a neuron's ability to respond to subsequent inputs. NEW & NOTEWORTHY We analyzed subthreshold activity preceding spikes in hippocampus and barrel cortex of awake mice. Aperiodic voltage ramps extending over tens to hundreds of milliseconds consistently precede and facilitate spikes, in a manner dependent on both their amplitude and their duration. These voltage ramps represent a "mesoscale" activated state that gates spike production in vivo., (Copyright © 2017 the American Physiological Society.)

Neuronal activity is energy demanding and coupled to cellular metabolism. In this study, we investigated the effects of glycolytic inhibition with 2-deoxy-d-glucose (2-DG) on basal membrane properties, spontaneous neuronal firing, and epileptiform network bursts in hippocampal slices. The effect of glycolytic inhibition on basal membrane properties was examined in hippocampal CA1 neurons, which are not ordinarily active spontaneously. Intracellular application of 2-DG did not significantly alter the membrane input resistance, action-potential threshold, firing pattern, or input-output relationship of these neurons compared with simultaneously recorded neighboring neurons without intracellular 2-DG. The effect of glycolytic inhibition on neuronal firing was tested in spontaneously active hippocampal neurons (CA3) when synaptic transmission was left intact or blocked with AMPA, NMDA, and GABA A receptor antagonists (DNQX, APV, and bicuculline, respectively). Under both conditions (synaptic activity intact or blocked), bath application of 2-DG (2 mM) blocked spontaneous firing in ~2/3 (67 and 71%, respectively) of CA3 pyramidal neurons. In contrast, neuronal firing of CA3 neurons persisted when 2-DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing. The effects of 2-DG on epileptiform network bursts in area CA3 were tested in Mg 2+ -free medium containing 50 µM 4-aminopyridine. Bath application of 2-DG abolished these epileptiform bursts in a dose-dependent and all-or-none manner. Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2-DG can effectively abrogate epileptiform activity. NEW & NOTEWORTHY Neuronal activity is highly energy demanding and coupled to cellular metabolism. In this study, we demonstrate that glycolytic inhibition with 2-deoxy-d-glucose (2-DG) effectively suppresses spontaneous neuronal firing and epileptiform bursts in hippocampal slices. These data suggest that an altered metabolic state can profoundly affect cellular and network excitability, and that the glycolytic inhibitor 2-DG may hold promise as a novel treatment of drug-resistant epilepsy., (Copyright © 2017 the American Physiological Society.)

Experimental and theoretical studies demonstrate that neuronal gamma oscillations crucially depend on interneurons, but current models do not consider the diversity of known interneuron subtypes. Moreover, in CA1 of the hippocampus, experimental evidence indicates the presence of multiple gamma oscillators, two of which may be coordinated by differing interneuron populations. In this article, we show that models of networks with competing interneuron populations with different postsynaptic effects are sufficient to generate, within CA1, distinct oscillatory regimes. We find that strong mutual inhibition between the interneuron populations permits distinct fast and slow gamma states, whereas weak mutual inhibition generates mixed gamma states. We develop idealized firing rate models to illuminate dynamic properties of these competitive gamma networks, and reinforce these concepts with basic spiking models. The models make several explicit predictions about gamma oscillators in CA1. Specifically, interneurons of different subtype phase-lock to different gamma states, and one population of interneurons is silenced and the other active during fast and slow gamma events. Finally, mutual inhibition between interneuron populations is necessary to generate distinct gamma states. Previous experimental studies indicate that fast and slow gamma oscillations reflect different information processing modes, although it is unclear whether these rhythms are intrinsic or imposed. The models outlined demonstrate that basic architectures can locally generate these oscillations, as well as capture other features of fast and slow gamma, including theta-phase preference and spontaneous transitions between gamma states. These models may extend to describe general dynamics in networks with diverse interneuron populations. NEW & NOTEWORTHY The oscillatory coordination of neural signals is crucial to healthy brain function. We have developed an idealized neuronal model that generates distinct fast and slow gamma oscillations, a known feature of the rodent hippocampus. Our work provides a mechanism of this phenomenon, as well as a theoretical framework for future experiments concerning hippocampal gamma. It moreover offers a tractable model of competitive gamma oscillations that is generalizable across the nervous system., (Copyright © 2017 the American Physiological Society.)

The subthreshold activity of hippocampal CA1 pyramidal neurons is regulated by the persistent sodium current (I NaP ) and the h-current (I h ), carried by tetrodotoxin-sensitive sodium channels and hyperpolarization-activated cyclic-nucleotide-gated channels, respectively. Recently, Yamada-Hanff and Bean (J Neurophysiol 114: 2376-2389, 2015) used pharmacological methods to discern the roles of I h and I NaP at subthreshold voltages during naturalistic stimuli. We discuss these findings in the context of dorsoventral heterogeneity in the hippocampus and suggest further applications of the method., (Copyright © 2016 the American Physiological Society.)

Rapid transmembrane flow of sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an "intermediate inactivation" (II) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials (V0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential, and recovery of II became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of INa decay corresponding to II and IS with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 10(2)-ms timescale, suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that II affects important aspects of hippocampal neuron response and may provide a drug target for sodium channel modulation., (Copyright © 2016 the American Physiological Society.)

We used dynamic clamp and action potential clamp techniques to explore how currents carried by tetrodotoxin-sensitive sodium channels and HCN channels (Ih) regulate the behavior of CA1 pyramidal neurons at resting and subthreshold voltages. Recording from rat CA1 pyramidal neurons in hippocampal slices, we found that the apparent input resistance and membrane time constant were strongly affected by both conductances, with Ih acting to decrease apparent input resistance and time constant and sodium current acting to increase both. We found that both Ih and sodium current were active during subthreshold summation of artificial excitatory postsynaptic potentials (EPSPs) generated by dynamic clamp, with Ih dominating at less depolarized voltages and sodium current at more depolarized voltages. Subthreshold sodium current-which amplifies EPSPs-was most effectively recruited by rapid voltage changes, while Ih-which blunts EPSPs-was maximal for slow voltage changes. The combined effect is to selectively amplify rapid EPSPs. We did similar experiments in mouse CA1 pyramidal neurons, doing voltage-clamp experiments using experimental records of action potential firing of CA1 neurons previously recorded in awake, behaving animals as command voltages to quantify flow of Ih and sodium current at subthreshold voltages. Subthreshold sodium current was larger and subthreshold Ih was smaller in mouse neurons than in rat neurons. Overall, the results show opposing effects of subthreshold sodium current and Ih in regulating subthreshold behavior of CA1 neurons, with subthreshold sodium current prominent in both rat and mouse CA1 pyramidal neurons and additional regulation by Ih in rat neurons., (Copyright © 2015 the American Physiological Society.)

Goal-directed and habit-based behaviors are driven by multiple but dissociable decision making systems involving several different brain areas, including the hippocampus and dorsal striatum. On repetitive tasks, behavior transitions from goal directed to habit based with experience. Hippocampus has been implicated in initial learning and dorsal striatum in automating behavior, but recent studies suggest that subregions within the dorsal striatum have distinct roles in mediating habit-based and goal-directed behavior. We compared neural activity in the CA1 region of hippocampus with anterior dorsolateral and posterior dorsomedial striatum in rats on a spatial choice task, in which subjects experienced reward delivery changes that forced them to adjust their behavioral strategy. Our results confirm the importance of the hippocampus in evaluating predictive steps during goal-directed behavior, while separate circuits in the basal ganglia integrated relevant information during automation of actions and recognized when new behaviors were needed to continue obtaining rewards., (Copyright © 2015 the American Physiological Society.)

Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior., (Copyright © 2015 the American Physiological Society.)

Emerging human, animal, and computational evidence suggest that, within the hippocampus, stored memories are compared with current sensory input to compute novelty, i.e., detecting when inputs deviate from expectations. Hippocampal subfield CA1 is thought to detect mismatches between past and present, and detected novelty is thought to modulate encoding processes, providing a mechanism for gating the entry of information into memory. Using high-resolution functional MRI, we examined human hippocampal subfield and medial temporal lobe cortical activation during prediction violations within a sequence of events unfolding over time. Subjects encountered sequences of four visual stimuli that were then reencountered in the same temporal order (Repeat) or a rearranged order (Violation). Prediction strength was manipulated by varying whether the sequence was initially presented once (Weak) or thrice (Strong) prior to the critical Repeat or Violation sequence. Analyses of blood oxygen level-dependent signals revealed that task-responsive voxels in anatomically defined CA1, CA23/dentate gyrus, and perirhinal cortex were more active when expectations were violated than when confirmed. Additionally, stronger prediction violations elicited greater activity than weaker violations in CA1, and CA1 contained the greatest proportion of voxels displaying this prediction violation pattern relative to other medial temporal lobe regions. Finally, a memory test with a separate group of subjects showed that subsequent recognition memory was superior for items that had appeared in prediction violation trials than in prediction confirmation trials. These findings indicate that CA1 responds to temporal order prediction violations, and that this response is modulated by prediction strength., (Copyright © 2015 the American Physiological Society.)

The dorsal and ventral hippocampi are functionally and anatomically distinct. Recently, we reported that dorsal Cornu Ammonis area 1 (CA1) neurons have a more hyperpolarized resting membrane potential and a lower input resistance and fire fewer action potentials for a given current injection than ventral CA1 neurons. Differences in the hyperpolarization-activated cyclic nucleotide-gated cation conductance between dorsal and ventral neurons have been reported, but these differences cannot fully account for the different resting properties of these neurons. Here, we show that coupling of A1 adenosine receptors (A1ARs) to G-protein-coupled inwardly rectifying potassium (GIRK) conductance contributes to the intrinsic membrane properties of dorsal CA1 neurons but not ventral CA1 neurons. The block of GIRKs with either barium or the more specific blocker Tertiapin-Q revealed that there is more resting GIRK conductance in dorsal CA1 neurons compared with ventral CA1 neurons. We found that the higher resting GIRK conductance in dorsal CA1 neurons was mediated by tonic A1AR activation. These results demonstrate that the different resting membrane properties between dorsal and ventral CA1 neurons are due, in part, to higher A1AR-mediated GIRK activity in dorsal CA1 neurons., (Copyright © 2015 the American Physiological Society.)

An increase in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel conductance reduces input resistance, whereas the consequent increase in the inward h current depolarizes the membrane. This results in a delicate and unique conductance-current balance triggered by the expression of HCN channels. In this study, we employ experimentally constrained, morphologically realistic, conductance-based models of hippocampal neurons to explore certain aspects of this conductance-current balance. First, we found that the inclusion of an experimentally determined gradient in A-type K(+) conductance, but not in M-type K(+) conductance, tilts the HCN conductance-current balance heavily in favor of conductance, thereby exerting an overall restorative influence on neural excitability. Next, motivated by the well-established modulation of neuronal excitability by synaptically driven high-conductance states observed under in vivo conditions, we inserted thousands of excitatory and inhibitory synapses with different somatodendritic distributions. We measured the efficacy of HCN channels, independently and in conjunction with other channels, in altering resting membrane potential (RMP) and input resistance (Rin) when the neuron received randomized or rhythmic synaptic bombardments through variable numbers of synaptic inputs. We found that the impact of HCN channels on average RMP, Rin, firing frequency, and peak-to-peak voltage response was severely weakened under high-conductance states, with the impinging synaptic drive playing a dominant role in regulating these measurements. Our results suggest that the debate on the role of HCN channels in altering excitability should encompass physiological and pathophysiological neuronal states under in vivo conditions and the spatiotemporal interactions of HCN channels with other channels., (Copyright © 2015 the American Physiological Society.)

Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD., (Copyright © 2014 the American Physiological Society.)

Endocannabinoids (eCBs) released from postsynaptic neurons mediate retrograde suppression of neurotransmitter release at central synapses. eCBs are crucial for establishing proper synaptic connectivity in the developing nervous system. Mobilization of eCBs is driven either by a rise in intracellular Ca(2+) (depolarization-induced suppression of inhibition, DSI) or postsynaptic G protein-coupled receptors (GPCRs) that activate phospholipase C beta (PLCβ). To determine whether eCB mobilization changes between neonatal and juvenile ages, we used whole cell voltage-clamp recordings of CA1 neurons from rat hippocampal slices at postnatal days 1-18 (neonatal) and 19-43 (juvenile), because many neurophysiological parameters change dramatically between approximately postnatal days 18-20. We found that DSI was slightly greater in juveniles than in neonates, while eCB mobilization stimulated by GPCRs was unchanged. However, when DSI was elicited during GPCR activation, its increase was much greater in juveniles, suggesting that eCB mobilization caused by the synergy between the Ca(2+) and GPCR pathways is developmentally upregulated. Western blotting revealed significant increases in both metabotropic type glutamate receptor 5 (mGluR5) and PLCβ1 proteins in juveniles compared with neonates. Responses to pharmacological activation or inhibition of PLC implied that eCB upregulation is associated with a functional increase in PLC activity. We conclude that synergistic eCB mobilization in hippocampal CA1 neurons is greater in juveniles than in neonates, and that this may result from increases in the mGluR5-PLCβ1 eCB pathway. The data enhance our understanding of the developmental regulation of the eCB system and may provide insight into diseases caused by improper cortical wiring, or the impact of cannabis exposure during development., (Copyright © 2014 the American Physiological Society.)

Hippocampal long-term potentiation (LTP) is a model system for studying cellular mechanisms of learning and memory. Recent interest in mechanisms underlying the advantage of spaced over massed learning has prompted investigation into the effects of distributed episodes of LTP induction. The amount of LTP induced in hippocampal area CA1 by one train (1T) of theta-burst stimulation (TBS) in young Sprague-Dawley rats was further enhanced by additional bouts of 1T given at 1-h intervals. However, in young Long-Evans (LE) rats, 1T did not initially saturate LTP. Instead, a stronger LTP induction paradigm using eight trains of TBS (8T) induced saturated LTP in hippocampal slices from both young and adult LE rats as well as adult mice. The saturated LTP induced by 8T could be augmented by another episode of 8T following an interval of at least 90 min. The success rate across animals and slices in augmenting LTP by an additional episode of 8T increased significantly with longer intervals between the first and last episodes, ranging from 0% at 30- and 60-min intervals to 13-66% at 90- to 180-min intervals to 90-100% at 240-min intervals. Augmentation above initially saturated LTP was blocked by the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV). These findings suggest that the strength of induction and interval between episodes of TBS, as well as the strain and age of the animal, are important components in the augmentation of LTP., (Copyright © 2014 the American Physiological Society.)

Sleep is involved in memory consolidation. Current theories propose that sleep-dependent memory consolidation requires active communication between the hippocampus and neocortex. Indeed, it is known that neuronal activities in the hippocampus and various neocortical areas are correlated during slow-wave sleep. However, transitioning from wakefulness to slow-wave sleep is a gradual process. How the hippocampal-cortical correlation is established during the wakefulness-sleep transition is unknown. By examining local field potentials and multiunit activities in the rat hippocampus and visual cortex, we show that the wakefulness-sleep transition is characterized by sharp-wave ripple events in the hippocampus and high-voltage spike-wave events in the cortex, both of which are accompanied by highly synchronized multiunit activities in the corresponding area. Hippocampal ripple events occur earlier than the cortical high-voltage spike-wave events, and hippocampal ripple incidence is attenuated by the onset of cortical high-voltage spike waves. This attenuation leads to a temporary weak correlation in the hippocampal-cortical multiunit activities, which eventually evolves to a strong correlation as the brain enters slow-wave sleep. The results suggest that the hippocampal-cortical correlation is established through a concerted, two-step state change that first synchronizes the neuronal firing within each brain area and then couples the synchronized activities between the two regions., (Copyright © 2014 the American Physiological Society.)

Behavior-associated theta-frequency oscillation in the hippocampal network involves a patterned activation of place cells in the CA1, which can be accounted for by a somatic-dendritic interference model predicting the existence of an intrinsic dendritic oscillator. Here we describe an intrinsic oscillatory mechanism in apical dendrites of in vitro CA1 pyramidal cells, which is induced by suprathreshold depolarization and consists of rhythmic firing of slow spikes in the theta-frequency band. The incidence of slow spiking (29%) increased to 78% and 100% in the presence of the β-adrenergic agonist isoproterenol (2 μM) or 4-aminopyridine (2 mM), respectively. Prior depolarization facilitated the induction of slow spiking. Applied electrical field polarization revealed a distal dendritic origin of slow spikes. The oscillations were largely insensitive to tetrodotoxin, but blocked by nimodipine (10 μM), indicating that they depend on activation of L-type Ca2+ channels. Antagonists of T-, R-, N-, and P/Q-type Ca2+ channels had no detectable effect. The slow spike dimension and frequency was sensitive to 4-aminopyridine (0.1-2 mM) and TEA (10 mM), suggesting the contribution from voltage-dependent K+ channels to the oscillation mechanism. α-Dendrotoxin (10 μM), stromatoxin (2 μM), iberiotoxin (0.2 μM), apamin (0.5 μM), linorpidine (30 μM), and ZD7288 (20 μM) were without effect. Oscillations induced by sine-wave current injection or theta-burst synaptic stimulation were voltage-dependently attenuated by nimodipine, indicating an amplifying function of L-type Ca2+ channels on imposed signals. These results show that the apical dendrites have intrinsic oscillatory properties capable of generating rhythmic voltage fluctuations in the theta-frequency band., (Copyright © 2014 the American Physiological Society.)

GluA2-lacking, calcium-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) have unique properties, but their presence at excitatory synapses in pyramidal cells is controversial. We have tested certain predictions of the model that such receptors are present in CA1 cells and show here that the polyamine spermine, but not philanthotoxin, causes use-dependent inhibition of synaptically evoked excitatory responses in stratum radiatum, but not s. oriens, in cultured and acute hippocampal slices. Stimulation of single dendritic spines by photolytic release of caged glutamate induced an N-methyl-d-aspartate receptor-independent, use- and spermine-sensitive calcium influx only at apical spines in cultured slices. Bath application of glutamate also triggered a spermine-sensitive influx of cobalt into CA1 cell dendrites in s. radiatum. Responses of single apical, but not basal, spines to photostimulation displayed prominent paired-pulse facilitation (PPF) consistent with use-dependent relief of cytoplasmic polyamine block. Responses at apical dendrites were diminished, and PPF was increased, by spermine. Intracellular application of pep2m, which inhibits recycling of GluA2-containing AMPARs, reduced apical spine responses and increased PPF. We conclude that some calcium-permeable, polyamine-sensitive AMPARs, perhaps lacking GluA2 subunits, are present at synapses on apical dendrites of CA1 pyramidal cells, which may allow distinct forms of synaptic plasticity and computation at different sets of excitatory inputs., (Copyright © 2014 the American Physiological Society.)

Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However, it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent, but not preadolescent, CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect on backpropagation is restricted to distal regions of apical dendrites (>200 μm) and mediated by α5-containing GABA(A) receptors. Direct dendritic recordings demonstrate α5-mediated tonic GABA(A) currents in adolescent neurons which can modulate BAPs. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally increasing or localized distal expression of dendritic α5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic α5 inhibition in a dendritic region-specific and developmentally regulated manner., (Copyright © 2014 the American Physiological Society.)

Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60-90 Hz) decreased and the low-gamma power (30-45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated.

Disruptions of endoplasmic reticulum (ER) Ca(2+) homeostasis are heavily linked to neuronal pathology. Depletion of ER Ca(2+) stores can result in cellular dysfunction and potentially cell death, although adaptive processes exist to aid in survival. We examined the age and region dependence of one postulated, adaptive response to ER store-depletion (SD), hyperpolarization-activated cation-nonspecific (h)-channel plasticity in neurons of the dorsal and ventral hippocampus (DHC and VHC, respectively) from adolescent and adult rats. With the use of whole-cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons, we observed a change in h-sensitive measurements in response to SD, induced by treatment with cyclopiazonic acid, a sarcoplasmic reticulum/ER Ca(2+)-ATPase blocker. We found that whereas DHC and VHC neurons in adolescent animals respond to SD with a perisomatic expression of SD h plasticity, adult animals express SD h plasticity with a dendritic and somatodendritic locus of plasticity in DHC and VHC neurons, respectively. Furthermore, SD h plasticity in adults was dependent on membrane potential and on the activation of L-type voltage-gated Ca(2+) channels. These results suggest that cellular responses to the impairment of ER function, or ER stress, are dependent on brain region and age and that the differential expression of SD h plasticity could provide a neural basis for region- and age-dependent disease vulnerabilities.

Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

Hyperpolarization-activated cyclic nucleotide-gated nonselective cation channels (HCN or h-channels) are important regulators of neuronal physiology contributing to passive membrane properties, such as resting membrane potential and input resistance (R(N)), and to intrinsic oscillatory activity and synaptic integration. The correct membrane targeting of h-channels is regulated in part by the auxiliary h-channel protein TRIP8b. The genetic deletion of TRIP8b results in a loss of functional h-channels, which affects the postsynaptic integrative properties of neurons. We investigated the impact of TRIP8b deletion on long-term potentiation (LTP) at the two major excitatory inputs to CA1 pyramidal neurons: Schaffer collateral (SC) and perforant path (PP). We found that SC LTP was not significantly different between neurons from wild-type and TRIP8b-knockout mice. There was, however, significantly more short-term potentiation in knockout neurons. We also found that the persistent increase in h-current (I(h)) that normally occurs after LTP induction was absent in knockout neurons. The lack of I(h) plasticity was not restricted to activity-dependent induction, because the depletion of intracellular calcium stores also failed to produce the expected increase in I(h). Interestingly, pairing of SC and PP inputs resulted in a form of LTP in knockout neurons that did not occur in wild-type neurons. These results suggest that the physiological impact of TRIP8b deletion is not restricted to the integrative properties of neurons but also includes both synaptic and intrinsic plasticity.

In the hippocampus, activity-dependent changes of synaptic transmission and spike-timing coordination are thought to mediate information processing for the purpose of memory formation. Here, we investigated the self-tuning of intrinsic excitability and spiking reliability by CA1 hippocampal pyramidal cells via changes of their GABAergic inhibitory inputs and endocannabinoid (eCB) signaling. Firing patterns of CA1 place cells, when replayed in vitro, induced an eCB-dependent transient reduction of spontaneous GABAergic activity, sharing the main features of depolarization-induced suppression of inhibition (DSI), and conditioned a transient improvement of spike-time precision during consecutive burst discharges. When evaluating the consequences of DSI on excitatory postsynaptic potential (EPSP)-spike coupling, we found that transient reductions of uncorrelated (spontaneous) or correlated (feedforward) inhibition improved EPSP-spike coupling probability. The relationship between EPSP-spike-timing reliability and inhibition was, however, more complex: transient reduction of correlated (feedforward) inhibition disrupted or improved spike-timing reliability according to the initial spike-coupling probability. Thus eCB-mediated tuning of pyramidal cell spike-time precision is governed not only by the initial level of global inhibition, but also by the ratio between spontaneous and feedforward GABAergic activities. These results reveal that eCB-mediated self-tuning of spike timing by the discharge of pyramidal cells can constitute an important contribution to place-cell assemblies and memory formation in the hippocampus.

The mechanisms behind the therapeutic effects of electrical stimulation of the brain in epilepsy and other disorders are poorly understood. Previous studies in vitro have shown that uniform electric fields can suppress epileptiform activity through a direct polarizing effect on neuronal membranes. Such an effect depends on continuous DC stimulation with unbalanced charge. Here we describe a suppressive effect of a brief (10 ms) DC field on stimulus-evoked epileptiform activity in rat hippocampal brain slices exposed to Cs(+) (3.5 mM). This effect was independent of field polarity, was uncorrelated to changes in synchronized population activity, and persisted during blockade of synaptic transmission with Cd(2+) (500 μM). Antagonists of A(1), P(2X), or P(2Y) receptors were without effect. The suppressive effect depended on the alignment of the external field with the somato-dendritic axis of CA1 pyramidal cells; however, temporal coincidence with the epileptiform activity was not essential, as suppression was detectable for up to 1 s after the field. Pyramidal cells, recorded during epileptiform activity, showed decreased discharge duration and truncation of depolarizing plateau potentials in response to field application. In the absence of hyperactivity, the applied field was followed by slow membrane potential changes, accompanied by decreased input resistance and attenuation of the depolarizing afterpotential following action potentials. These effects recovered over a 1-s period. The study suggests that a brief electric field induces a prolonged suppression of epileptiform activity, which can be related to changes in neuronal membrane properties, including attenuation of signals depending on the persisting Na(+) current.

Phase-resetting properties of neurons determine their functionality as integrators (type 1) vs. resonators (type 2), as well as their synchronization tendencies. We introduce a novel, bias-correction method to estimate the infinitesimal phase-resetting curve (iPRC) and confirm type 1 excitability in hippocampal pyramidal CA1 neurons in vitro by two independent methods. First, PRCs evoked using depolarizing pulses consisted only of advances, consistent with type 1. Second, the frequency/current (f/I) plots showed no minimum frequency, again consistent with type 1. Type 1 excitability was also confirmed by the absence of a resonant peak in the interspike interval histograms derived from the f/I data. The PRC bias correction assumed that the distribution of noisy phase resetting is truncated, because an input cannot advance a spike to a point in time before the input (the causal limit) and successfully removed the statistical bias for delays in the null PRC in response to zero-magnitude input by computing the phase resetting as the mean of the untruncated distribution. The PRC for depolarization peaked at late phases and decreased to zero by the end of the cycle, whereas delays observed in response to hyperpolarization increased monotonically. The bias correction did not affect this difference in shape, which was due instead to the causal limit obscuring the iPRC for depolarization but not hyperpolarization. Our results suggest that weak periodic hyperpolarizing drive can theoretically entrain CA1 pyramidal neurons at any phase but that strong excitation will preferentially phase-lock them with zero time lag.

Phase response curves (PRCs) are a simple model of how a neuron's spike time is affected by synaptic inputs. PRCs are useful in predicting how networks of neurons behave when connected. One challenge in estimating a neuron's PRCs experimentally is that many neurons do not have stationary firing rates. In this article we introduce a new method to estimate PRCs as a function of firing rate of the neuron. We call the resulting model a parameterized PRC (pPRC). Experimentally, we perturb the neuron applying a current with two parts: 1) a current held constant between spikes but changed at the onset of a spike, used to make the neuron fire at different rates, and 2) a pulse to emulate a synaptic input. A model of the applied constant current and the history is made to predict the interspike interval (ISI). A second model is then made to fit the modulation of the spike time from the expected ISI by the pulsatile stimulus. A polynomial with two independent variables, the stimulus phase and the expected ISI, is used to model the pPRC. The pPRC is validated in a computational model and applied to pyramidal neurons from the CA1 region of the hippocampal slices from rat. The pPRC can be used to model the effect of changing firing rates on network synchrony. It can also be used to characterize the effects of neuromodulators and genetic mutations (among other manipulations) on network synchrony. It can also easily be extended to account for more variables.

The rodent hippocampus can be divided into dorsal (DHC) and ventral (VHC) domains on the basis of behavioral, anatomical, and biochemical differences. Recently, we reported that CA1 pyramidal neurons from the VHC were intrinsically more excitable than DHC neurons, but the specific ionic conductances contributing to this difference were not determined. Here we investigated the hyperpolarization-activated current (I(h)) and the expression of HCN1 and HCN2 channel subunits in CA1 pyramidal neurons from the DHC and VHC. Measurement of Ih with cell-attached patches revealed a significant depolarizing shift in the V(1/2) of activation for dendritic h-channels in VHC neurons (but not DHC neurons), and ultrastructural immunolocalization of HCN1 and HCN2 channels revealed a significantly larger HCN1-to-HCN2 ratio for VHC neurons (but not DHC neurons). These observations suggest that a shift in the expression of HCN1 and HCN2 channels drives functional changes in I(h) for VHC neurons (but not DHC neurons) and could thereby significantly alter the capacity for dendritic integration of these neurons.