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The hippocampus (HP) receives neurochemically diverse inputs from the raphe nuclei, including glutamatergic fibers characterized by the expression of the vesicular glutamate transporter VGLUT3. These raphe-HP VGLUT3 (VGLUT3HP) projections have been suggested to play a critical role in HP functions, yet a complete anatomical overview of raphe VGLUT3 projections to the forebrain, and in particular the HP, is lacking. Using anterograde viral tracing, we describe largely non-overlapping VGLUT3-positive projections from the dorsal raphe (DR) and median raphe (MnR) to the forebrain, with the HP receiving inputs from the MnR. A limited subset of forebrain regions such as the amygdaloid complex, claustrum and hypothalamus receive projections from both the DR and MnR that remain largely segregated. This highly complementary anatomical pattern suggests contrasting roles for DR and MnR VGLUT3 neurons. To further analyse the topography of VGLUT3 raphe projections to the HP, we used retrograde tracing and found that VGLUT3HP neurons distribute over several raphe sub-regions (including the MnR, paramedian raphe and B9 nucleus) and lack co-expression of serotonergic markers. Strikingly, two-color retrograde tracing unraveled two parallel streams of VGLUT3-positive projections targeting the dorsal and ventral poles of the HP. These results demonstrate highly organized and segregated VGLUT3-positive projections to the HP, suggesting independent modulation of HP functions such as spatial memory and emotion-related behavior.

Conducting polymer coatings on metal electrodes are an efficient solution to improve neural signal recording and stimulation, due to their mixed electronic-ionic conduction and biocompatibility. To date, only a few studies have been reported on conducting polymer coatings on metallic wire electrodes for muscle signal recording. Chronic muscle signal recording of freely moving animals can be challenging to acquire with coated electrodes, due to muscle movement around the electrode that can increase instances of coating delamination and device failure. The poor adhesion of conducting polymers to some inorganic substrates and the possible degradation of their electrochemical properties after harsh treatments, such as sterilization, or during implantation limits their use for biomedical applications. Here, we demonstrate the mechanical and electrochemical stability of the conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT) doped with LiClO4, deposited on stainless steel multistranded wire electrodes for invasive muscle signal recording in mice. The mechanical and electrochemical stability was achieved by tuning the electropolymerization conditions. PEDOT-coated and bare stainless steel electrodes were implanted in the neck muscle of five mice for electromyographic (EMG) activity recording over a period of 6 weeks. The PEDOT coating improved the electrochemical properties of the stainless steel electrodes, lowering the impedance, resulting in an enhanced signal-to-noise ratio during in vivo EMG recording compared to bare electrodes.

Theta rhythm is a large 4–12 Hz oscillatory activity that is predominant during wake and REM (rapid eye movement) sleep in the hippocampus. Theta rhythm is generated by the interplay between neurons from the medial septum and entorhinal cortex, with local oscillators within the hippocampus. These intrinsic hippocampal oscillators arise from the interaction between pyramidal cells and specific subtypes of interneurons. Theta contributes to the formation of place cell assemblies important for memory and navigation. In addition, theta in hippocampus can control spiking and computations in other brain regions such as the prefrontal cortex, the amygdala, and striatum, and contribute to different cognitive tasks such as working memory, fear conditioning, motivation, and reward. As such, theta rhythm in hippocampus plays a critical role in providing spatial and contextual information locally and throughout the brain.

1.1. Background Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking infiltration of activated PBMCs into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS.1.2. Methods To establish our model, we first extracted PBMCs from rat spleen, then, immunologically primed PBMCs with lipopolysaccharide (LPS), followed by further activation with nigericin. Thereafter, we co-cultured these activated PBMCs with organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. We further targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 hours, we analyzed inflammation markers in the cortex and the hippocampus using semiquantitative immunofluorescence. In addition, we analyzed neuronal activity by whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons.1.3. Results In the cortex, co-culturing immunoreactive PBMCs treated with LPS + nigericin on top of OCHSCs upregulated inflammatory markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs (i.e. treated with LPS only), to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, protected them from neuroinflammation and hippocampal hyperexcitability.1.4. Conclusions Our study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.

Theta oscillations are essential for learning and memory, and their generation requires GABAergic interneurons. To better understand how theta is generated, we explored how parvalbumin (PV) and somatostatin (SOM) interneurons in CA1 stratum oriens/alveus fire during hippocampal theta and investigated synaptic mechanisms underlying their behavior. Combining the use of transgenic mice to visually identify PV and SOM interneurons and the intact hippocampal preparation that can generate theta oscillations in vitro without cholinergic agonists, we performed simultaneous field and whole-cell recordings. We found that PV interneurons uniformly fire strongly phase-locked to theta, whereas SOM neurons are more heterogeneous with only a proportion of cells displaying tight phase-locking. Differences in phase-locking strength could be explained by disparity in excitatory inputs received; PV neurons received significantly larger EPSCs compared with SOM neurons, and the degree of phase-locking in SOM neurons was significantly correlated with the size of EPSCs. In contrast, IPSC amplitude did not differ between cell types. We determined that the local CA1 rhythm plays a more dominant role in driving CA1 interneuron firing than afferent inputs from the CA3. Last, we show that PV and strongly phase-locked SOM neurons fire near the peak of CA1 theta, under the tight control of excitatory inputs that arise at a specific phase of each theta cycle. These results reveal a fundamental mechanism of neuronal phase-locking and highlight an important role of excitation from the local network in governing firing behavior during rhythmic network states. SIGNIFICANCE STATEMENT Rhythmic activity in the theta range (3–12 Hz) is important for proper functioning of the hippocampus, a brain area essential for learning and memory. To understand how theta rhythm is generated, we investigated how two types of inhibitory neurons, those that express parvalbumin and somatostatin, fire action potentials during theta in an in vitro preparation of the mouse hippocampus. We found that the amount of excitatory input they receive from the local network determines how closely their spikes follow the network theta rhythm. Our findings reveal an important role of local excitatory input in driving inhibitory neuron firing during rhythmic states and may have implications for diseases, such as epilepsy and Alzheimer9s disease, which affect the hippocampus and related areas.

International audience; Dopamine (DA) neurons in the ventral tegmental area (VTA) help mediate stress susceptibility and resilience. However, upstream mechanisms controlling these neurons remain unknown. Noradrenergic (NE) neurons in the locus coeruleus, implicated in the pathophysiology of depression, have direct connections within the VTA. Here we demonstrate that NE neurons regulate vulnerability to social defeat through inhibitory control of VTA DA neurons.

The nicotinic acetylcholine receptor alpha2 subunit (Chrna2) is a specific marker for oriens lacunosum-moleculare (OLM) interneurons in the dorsal CA1 region of the hippocampus. It was recently shown using a Chrna2-cre mice line that OLM interneurons can modulate entorhinal cortex and CA3 inputs and may therefore have an important role in gating, encoding, and recall of memory. In this study, we have used a combination of electrophysiology and optogenetics using Chrna2-cre mice to determine the role of Chrna2 interneurons in the subiculum area, the main output region of the hippocampus. We aimed to assess the similarities between Chrna2 subiculum and CA1 neurons in terms of the expression of interneuron markers, their membrane properties, and their inhibitory input to pyramidal neurons. We found that subiculum and CA1 dorsal Chrna2 cells similarly expressed the marker somatostatin and had comparable membrane and firing properties. The somas of Chrna2 cells in both regions were found in the deepest layer with axons projecting superficially. However, subiculum Chrna2 cells displayed more extensive projections with dendrites which occupied a significantly larger area than in CA1. The post-synaptic responses elicited by Chrna2 cells in pyramidal cells of both regions revealed comparable inhibitory responses elicited by GABAA receptors and, interestingly, GABAB receptor mediated components. This study provides the first in-depth characterization of Chrna2 cells in the subiculum, and suggests that subiculum and CA1 Chrna2 cells are generally similar and may play comparable roles in both sub-regions.

Neonates respond to hypoxia initially by increasing ventilation, and then by markedly decreasing both ventilation (hypoxic ventilatory decline) and oxygen consumption (hypoxic hypometabolism). This latter process, which vanishes with age, reflects a tight coupling between ventilatory and thermogenic responses to hypoxia. The neurological substrate of hypoxic hypometabolism is unclear, but it is known to be centrally mediated, with a strong involvement of the 5-hydroxytryptamine (5-HT, serotonin) system. To clarify this issue, we investigated the possible role of VGLUT3, the third subtype of vesicular glutamate transporter. VGLUT3 contributes to glutamate signalling by 5-HT neurons, facilitates 5-HT transmission and is expressed in strategic regions for respiratory and thermogenic control. We therefore assumed that VGLUT3 might significantly contribute to the response to hypoxia. To test this possibility, we analysed this response in newborn mice lacking VGLUT3 using anatomical, biochemical, electrophysiological and integrative physiology approaches. We found that the lack of VGLUT3 did not affect the histological organization of brainstem respiratory networks or respiratory activity under basal conditions. However, it impaired respiratory responses to 5-HT and anoxia, showing a marked alteration of central respiratory control. These impairments were associated with altered 5-HT turnover at the brainstem level. Furthermore, under cold conditions, the lack of VGLUT3 disrupted the metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia. We conclude that VGLUT3 expression is dispensable under basal conditions but is required for optimal response to hypoxic stress in neonates.

Three subtypes of vesicular glutamate transporters, named VGLUT1-3, accumulate glutamate into synaptic vesicles. In this study, the post-natal expression of VGLUT3 was determined with specific probes and antiserums in the rat brain and compared with that of VGLUT1 and VGLUT2. The expression of VGLUT1 and VGLUT2 increases linearly during post-natal development. In contrast, VGLUT3 developmental pattern appears to have a more or less biphasic profile. A first peak of expression is centered around post-natal day 10 (P10) while the second one is reached in the adult brain. Between P1 and P15, VGLUT3 is observed in the frontal brain (striatum, accumbens, and hippocampus) and in the caudal brain (colliculi, pons and cerebellum). During a second phase extending from P15 to adulthood, the labeling of the caudal brain fades away. The adult pattern is reached at P21. We further analyzed the transient expression of VGLUT3 in the cerebellum and found it to correspond to a temporary expression in Purkinje cells. At P10 VGLUT3 immunoreactivity was present both in the soma and terminals of Purkinje cells (PC), where it colocalized with the vesicular inhibitory amino acid transporter (VIAAT). In agreement with data from the literature [Gillespie, D.C., Kim, G., Kandler, K., 2005. Inhibitory synapses in the developing auditory system are glutamatergic. Nat. Neurosci. 8, 332-338], our results suggest that during the first 2 weeks of post-natal life PC may have the potential to transiently release simultaneously GABA and glutamate.

The hippocampus is a heavily studied brain structure due to its involvement in learning and memory. Detailed models of excitatory, pyramidal cells in hippocampus have been developed using a range of experimental data. These models have been used to help us understand, for example, the effects of synaptic integration and voltage gated channel densities and distributions on cellular responses. However, these cellular outputs need to be considered from the perspective of the networks in which they are embedded. Using modeling approaches, if cellular representations are too detailed, it quickly becomes computationally unwieldy to explore large network simulations. Thus, simple models are preferable, but at the same time they need to have a clear, experimental basis so as to allow physiologically based understandings to emerge. In this article, we describe the development of simple models of CA1 pyramidal cells, as derived in a well-defined experimental context of an intact, whole hippocampus preparation expressing population oscillations. These models are based on the intrinsic properties and frequency-current profiles of CA1 pyramidal cells, and can be used to build, fully examine, and analyze large networks.

Activity flow through the hippocampus is thought to arise exclusively from unidirectional excitatory synaptic signaling from CA3 to CA1 to the subiculum. Theta rhythms are important for hippocampal synchronization during episodic memory processing; thus, it is assumed that theta rhythms follow these excitatory feedforward circuits. To the contrary, we found that theta rhythms generated in the rat subiculum flowed backward to actively modulate spike timing and local network rhythms in CA1 and CA3. This reversed signaling involved GABAergic mechanisms. However, when hippocampal circuits were physically limited to a lamellar slab, CA3 outputs synchronized CA1 and the subiculum using excitatory mechanisms, as predicted by classic hippocampal models. Finally, analysis of in vivo recordings revealed that this reversed theta flow was most prominent during REM sleep. These data demonstrate that communication between CA3, CA1 and the subiculum is not exclusively unidirectional or excitatory and that reversed inhibitory theta signaling also contributes to intrahippocampal synchrony.

From several experimental and modeling studies, it has become apparent that networks of parvalbumin-positive (PV+), fast-firing interneurons play an essential role in generating population gamma rhythms [1]. Many features of these perisomatically-inhibiting PV+ cell networks influence the generation of gamma oscillations, a number of which have been explored in network models [2,3]. These include the synaptic delay, the decay time constant of the postsynaptic conductance, and whether the reversal potential is hyperpolarizing or shunting. While it is clear that all these features affect whether and how much coherence occurs at gamma frequencies, it is much less clear which features (i.e. parameters and parameter balances) may be essential in various biological contexts. To address this, we used our previously constructed network model of hippocampal CA1 PV+ cells [4]. Network size, connectivity, and cellular components would all be expected to affect the network dynamics. Thus, experimental data from an intact hippocampus in vitro was used to obtain a clear biological context, and importantly, the amount of input that these cells receive during ongoing theta population activities was estimated. Using these cellular components and input characteristics, we found that coherent gamma oscillations could emerge within experimental constraints for particular parameter balances. Here we investigate the effect of appropriately sized and connected networks. Each cell in the network received excitatory input (Iapplied ), which was heterogeneous across cells, and synaptic inhibition from presynaptic interneurons, which had a particular maximal conductance value (gPV). We systematically varied gPV and Iapplied within the experimentally determined ranges, and determined the coherence of the network model population firing and the network frequency for each combination of these values. For each of these network simulation sets, we also varied the connectivity probability as well as network size to explore how these factors affect the network’s ability to produce coherent network firing. We find that when our connection probability is similar to what has been found experimentally, our networks exhibit a sharp transition from random firing to network coherence with only a small change in Iapplied. However, as connectivity in the network is increased beyond experimentally estimated values, this sharp transition disappears. Instead, a larger window of coherence is achieved, but with a smooth transition from random to coherent firing. Similarly, decreasing the network size increases the window of coherent firing, and while these sharp transitions remain for changing network sizes, the parameter regimes in which they occur changes significantly when the network size becomes much smaller than experimental estimates. Our work indicates that CA1 fastspiking PV+ networks are capable of producing gamma population rhythms, and that perturbation in and out of coherent states can occur abruptly given the sharp transitions obtained in our network simulations. Since our simulations approximate a biological context, it may be that gating in and out of coherence is a design property to allow generation of theta/gamma network oscillations.

Our PV+ interneurons are represented with an Izhikevich-type model [2], and involve parameter values that are designed to approximate the cell’ si ntrinsic properties. To determine these parameters, spike characteristics and passive properties were extracted from wholecell patch clamp recordings of PV+ interneurons in the CA1 region of an intact hippocampal preparation in vitro. Our network model is composed of these individual PV+ cell models, and the network size, architecture, and synaptic properties are chosen to be consistent with those found in the literature. Recordings during emergent network oscillations [3] provided us with information about realistic firing rates and synaptic activity of PV+ interneurons. These firing rates, used in combination with the cell’s intrinsic frequency-current profile, provided physiological constraints on the amount of synaptic current the PV+ cells receive during these spontaneous network oscillations. Under voltage clamp, excitatory post-synaptic current peaks are used in our model as an upper bound on the range of synaptic input. We used this network model to determine whether coherent rhythms could be produced within experimental constraints. Our model produced intrinsic properties and spiking behaviors which approximated the experimentally determined membrane capacitance, resting membrane potential, threshold potential, spike width, spike peak potential, peak after-hyperpolarizing potential, and amount of adaptation. Model parameters were determined such that the slope of the model’s frequency-current profile and the model rheobase current were within the range of our experimental data. As such, we have produced a network model of PV+ interneurons that has direct links to cellular characteristics with model parameters that have clear biological interpretations. In addition, network simulations of our PV+ interneuron model produced coherent gamma output. Since the firing properties and network architecture of PV+ interneurons puts them in an ideal position to influence network activity, this cell type will likely remain a focus of experimentalists and modelers alike. A model such as ours, with clear links to biology, may be used as a platform to investigate the role of these fast-firing PV+ interneurons in network oscillations and behaviour.

International audience; Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans. We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness. In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls. Linkage-disequilibrium analysis suggested that the families have a distant common ancestor. The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role. In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse.

Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3(-/-) mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications.

SummaryHippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic connections and oscillates spontaneously at theta frequencies. Despite evidence suggesting that SOM interneurons are crucial for theta, optogenetic manipulation of these interneurons modestly influenced theta rhythm. However, SOM interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta.

Although hippocampal theta, a 4-12 Hz rhythm associated with episodic memory, has been studied extensively, the cellular mechanisms underlying its generation are unclear. OLM cells have been considered pacemakers of local CA1 theta [1], but recent experimental work has disputed this role [2]. The complex interactions that OLM cells have with other cell types, such as bistratified cells (BSCs) [3], make their contribution to network rhythms difficult to determine experimentally. One can address this issue using mathematical network models, which allow one to explore the contribution of specific cell populations and network connectivity in a simplified setting, and make predictions to guide further experimental work. Thus, we created a network model that is tied to experimental work on both the cellular and network level, and explored how cell interactions affect the power of local oscillations. We derived cellular properties from patch clamp recordings of fast-spiking parvalbumin-positive (PV+) interneurons – likely comprising basket cells (BCs), axo-axonic cells (AACs), and BSCs – and of somatostatin-positive putative OLM cells in the CA1 region of an intact hippocampus in vitro, and used these properties to constrain Izhikevich-type models of BCs/AACs, BSCs, and OLM interneurons. We constructed our network model with these individual cell models, and constrained network size, connectivity, and synaptic properties with experimental data. Experimental excitatory postsynaptic currents (EPSCs) recorded during endogenous CA1 theta oscillations were used to drive the various cell model populations, and we used a simple local field potential (LFP) model to integrate the effects of cell firing. To determine how the interactions between OLM cells and BSCs affect local theta rhythms, we explored how specific features of the network affected model LFP power. In addition, we simulated optogenetic experiments by silencing the OLM cell model population during the network rhythm. Spike characteristics and firing behaviors in our network models approximated those determined experimentally. Our models distinguish between regimes in which OLM cells minimally or strongly affect the power of network oscillations, and predict that the dis-inhibitory effect of OLM cells on BSC to pyramidal cell interactions plays a critical role in the power of network theta oscillations. When OLM to BSC model connections are not too strong, the OLM cells’ direct influence on pyramidal cells balances with its indirect dis-inhibitory effect (through the BSCs). In this case, when the OLM cell population is silenced, there is a compensatory effect on network power, and thus minimal change in power. However, when these OLM to BSC connections are stronger, the dis-inhibition of pyramidal cells does not balance with their direct influence, and thus silencing OLM cells has a stronger effect. This does not change when we consider various distributions of strengths in which the cell populations affect the LFP. Thus, our network models are able to make particular predictions that can be tested with optogenetics.

Theta oscillations are one of the most prominent and well-studied clocking mechanisms detected in the mammalian brain. Recorded from the hippocampus during R.E.M. sleep and exploratory behavior, these 3-12 Hz rhythms are thought to play a lead role in spatial navigation, episodic memory, and the timing of place cell firing [1]. Although these oscillations have been heavily studied, the mechanism(s) responsible for the generation of these rhythms remains unknown. A popular theory hypothesizes that pacemaker neurons in the medial septum drive hippocampal rhythms [1] , but recent research shows that in an intact hippocampus preparation in vitro, the CA1 hippocampal region possesses the necessary circuitry to generate intrinsic theta rhythms [2]. To determine the mechanism(s) underlying the generation of these CA1 hippocampal theta rhythms, we created a mathematical network model. Our mathematical network model is composed of four types of cells: pyramidal cells, fast-spiking parvalbumin-positive basket cells (PV+BCs), slow-spiking cholecystokinin-positive basket cells (CCK+BCs), and oriens – lacunosum-moleculare (O-LM) interneurons. Each cell type is represented by a single-compartment, conductance-based model, and intrahippocampal connections among the chosen cell types are modeled based on experimental data of known connectivities. In addition, intracellular data recorded from the CA1 region of the intact hippocampus in vitro was used in combination with mathematical extraction techniques [3,4] to determine the balance of synaptic excitation and inhibition in individual cell types during the theta rhythm. Thus, experimental recordings, data analysis, and modeling were combined to generate an understanding of the mechanism(s) involved in the CA1 hippocampal theta rhythm. Our network model produces robust theta rhythms and cellular phase relationships in accordance with the experimental data. Interestingly, we find that inhibitory input imposed on pyramidal cells from the PV+BCs is a critical component in the production of these theta rhythms because the existence of the rhythm is most sensitive to these inhibitory conductances. This finding is surprising, as research has focused on the role of PV+BCs in faster gamma rhythms (20-100 Hz). In addition, we extracted mean synaptic conductance values from intracellular recordings of PV+BC and somatostatin-expressing (putative O-LM) interneuron activity. These synaptic values indicate that from the quiescent relative to the active state of the CA1 theta rhythm, the PV+BCs undergo a more significant reduction in inhibition than the putative O-LM interneurons. Optogenetics will be used to test predictions about the role of individual interneuron types in the generation of CA1 hippocampal theta rhythms.