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Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

Long-term potentiation (LTP) is a synaptic mechanism involved in learning and memory. Experiments have shown that dendritic sodium spikes (Na-dSpikes) are required for LTP in the distal apical dendrites of CA1 pyramidal cells. On the other hand, LTP in perisomatic dendrites can be induced by synaptic input patterns that can be both subthreshold and suprathreshold for Na-dSpikes. It is unclear whether these results can be explained by one unifying plasticity mechanism. Here, we show in biophysically and morphologically realistic compartmental models of the CA1 pyramidal cell that these forms of LTP can be fully accounted for by a simple plasticity rule. We call it the voltage-based Event-Timing-Dependent Plasticity (ETDP) rule. The presynaptic event is the presynaptic spike or release of glutamate. The postsynaptic event is the local depolarization that exceeds a certain plasticity threshold. Our model reproduced the experimentally observed LTP in a variety of protocols, including local pharmacological inhibition of dendritic spikes by tetrodotoxin (TTX). In summary, we have provided a validation of the voltage-based ETDP, suggesting that this simple plasticity rule can be used to model even complex spatiotemporal patterns of long-term synaptic plasticity in neuronal dendrites. [ABSTRACT FROM AUTHOR]

Neocortical pyramidal neurons have many dendrites, and such dendrites are capable of, in isolation of one-another, generating a neuronal spike. It is also now understood that there is a large amount of dendritic growth during the first years of a humans life, arguably a period of prodigious learning. These observations inspire the construction of a local, stochastic algorithm based on an earlier stochastic, homeostatic, Hebbian developmental theory. Here we investigate the neurocomputational advantages and limits on this novel algorithm that combines dendritogenesis with supervised adaptive synaptogenesis. Neurons created with this algorithm have enhanced memory capacity, can avoid catastrophic interference (forgetting), and have the ability to unmix mixture distributions. In particular, individual dendrites develop within each class, in an unsupervised manner, to become feature-clusters that correspond to the mixing elements of class-conditional mixture distribution. Error-free classification is demonstrated with input perturbations up to 40%. Although discriminative problems are used to understand the capabilities of the stochastic algorithm and the neuronal connectivity it produces, the algorithm is in the generative class, it thus seems ideal for decisions that require generalization, i.e., extrapolation beyond previous learning. • Adaptive dendritic growth enhances memory capacity, avoiding catastrophic forgetting. • The stochastic algorithm encodes a conditional expectation at each synapse. • The algorithm is an extension of class supervised adaptive synaptogenesis. • Creating cluster centers, each dendrite develops in an unsupervised manner. [ABSTRACT FROM AUTHOR]

• Branch-constrained dendritic NMDA spikes can be suppressed by local hyperpolarization. • Branch-constrained hyperpolarization does not suppress NMDA spikes on other dendritic branches. • The local generation of NMDA spikes can induce LTP in a branch-selective manner. N-methyl- d -aspartate receptor-mediated (spikes can be causally linked to the induction of synaptic long-term potentiation (LTP) in hippocampal and cortical pyramidal cells. However, it is unclear if they regulate plasticity at a local or global scale in the dendritic tree. Here, we used dendritic patch-clamp recordings and calcium imaging to investigate the integrative properties of single dendrites of hippocampal CA3 cells. We show that local hyperpolarization of a single dendritic segment prevents NMDA spikes, their associated calcium transients, as well as LTP in a branch-specific manner. This result provides direct, causal evidence that the single dendritic branch can operate as a functional unit in regulating CA3 pyramidal cell plasticity. [ABSTRACT FROM AUTHOR]

Pyramidal neurons (PNs) are the most abundant cells of the neocortex and display a vast dendritic tree, divided into basal and apical compartments. Morphological and functional anomalies of PN dendrites are at the basis of virtually all neurological and mental disorders, including intellectual disability. Here, we provide evidence that the cognitive deficits observed in different types of intellectual disability might be sustained by different parts of the PN dendritic tree, or by a dysregulation of their interaction. [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation (rTMS) induces long-term changes of synapses, but the mechanisms behind these modifications are not fully understood. Although there has been progress in the development of multi-scale modeling tools, no comprehensive module for simulating rTMS-induced synaptic plasticity in biophysically realistic neurons exists.., Objective: We developed a modelling framework that allows the replication and detailed prediction of long-term changes of excitatory synapses in neurons stimulated by rTMS., Methods: We implemented a voltage-dependent plasticity model that has been previously established for simulating frequency-, time-, and compartment-dependent spatio-temporal changes of excitatory synapses in neuronal dendrites. The plasticity model can be incorporated into biophysical neuronal models and coupled to electrical field simulations., Results: We show that the plasticity modelling framework replicates long-term potentiation (LTP)-like plasticity in hippocampal CA1 pyramidal cells evoked by 10-Hz repetitive magnetic stimulation (rMS). This plasticity was strongly distance dependent and concentrated at the proximal synapses of the neuron. We predicted a decrease in the plasticity amplitude for 5 Hz and 1 Hz protocols with decreasing frequency. Finally, we successfully modelled plasticity in distal synapses upon local electrical theta-burst stimulation (TBS) and predicted proximal and distal plasticity for rMS TBS. Notably, the rMS TBS-evoked synaptic plasticity exhibited robust facilitation by dendritic spikes and low sensitivity to inhibitory suppression., Conclusion: The plasticity modelling framework enables precise simulations of LTP-like cellular effects with high spatio-temporal resolution, enhancing the efficiency of parameter screening and the development of plasticity-inducing rTMS protocols., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The dendrites of neocortical pyramidal neurons are excitable. However, it is unknown how synaptic inputs engage nonlinear dendritic mechanisms during sensory processing in vivo, and howthey in turn influence action potential output. Here, we provide a quantitative account of the relationship between synaptic inputs, nonlinear dendritic events, and action potential output. We developed a detailed pyramidal neuron model constrained by in vivo dendritic recordings. We drive thismodel with realistic input patterns constrained by sensory responses measured in vivo and connectivity measured in vitro. We show mechanistically that under realistic conditions, dendritic Na+ and NMDA spikes are the major determinants of neuronal output in vivo. We demonstrate that these dendritic spikes can be triggered by a surprisingly small number of strong synaptic inputs, in some cases even by single synapses. We predict that dendritic excitability allows the 1% strongest synaptic inputs of a neuron to control the tuning of its output. Active dendrites therefore allow smaller subcircuits consisting of only a few strongly connected neurons to achieve selectivity for specific sensory features. [ABSTRACT FROM AUTHOR]

Dendritic spikes facilitate neuronal computation and they have been reported to occur in various regions of the dendritic tree of cortical neurons. Spikes that occur only on a select few branches are particularly difficult to analyze especially in complex and intertwined dendritic arborizations where highly localized application of pharmacological blocking agents is not feasible. Here, we present a technique based on highly targeted dendrotomy to tease out and study dendritic spikes that occur in oblique branches of cortical layer five pyramidal neurons. We first analyze the effect of cutting dendrites in silico and then confirmed in vitro using an ultrafast laser scalpel. A dendritic spike evoked in an oblique branch manifests at the soma as an increase in the afterdepolarization (ADP). The spikes are branch-specific since not all but only a few oblique dendrites are observed to evoke spikes. Both our model and experiments show that cutting certain oblique branches, where dendritic spikes are evoked, curtailed the increase in the ADP. On the other hand, cutting neighboring oblique branches that do not evoke spikes maintained the ADP. Our results show that highly targeted dendrotomy can facilitate causal analysis of how branch-specific dendritic spikes influence neuronal output.

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here, we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na+ spike generation during PP-GC input. Inhibition of dendritic Na+ spikes impairs LTP induction at PP-GC synapse. These data suggest that dendritic spikes may constitute a key cellular mechanism for memory formation in the dentate gyrus.

What is the function of dendritic spikes? One might argue that they provide conditions for neuronal plasticity or that they are essential for neural computation. However, despite a long history of dendritic research, the physiological relevance of dendritic spikes in brain function remains unknown. This could stem from the fact that most studies on dendrites have been performed in vitro. Fortunately, the emergence of novel techniques such as improved two-photon microscopy, genetically encoded calcium indicators (GECIs), and optogenetic tools has provided the means for vital breakthroughs in in vivo dendritic research. These technologies enable the investigation of the functions of dendritic spikes in behaving animals, and thus, help uncover the causal relationship between dendritic spikes, and sensory information processing and synaptic plasticity. Understanding the roles of dendritic spikes in brain function would provide mechanistic insight into the relationship between the brain and the mind. In this review article, we summarize the results of studies on dendritic spikes from a historical perspective and discuss the recent advances in our understanding of the role of dendritic spikes in sensory perception. [ABSTRACT FROM AUTHOR]

Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation, short-term postsynaptic plasticity (STPP), has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain. [ABSTRACT FROM AUTHOR]

Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na+ spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na+ spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow.

Spiny neurons of amygdala, striatum, and cerebral cortex share four interesting features: [1] they are the most abundant cell type within their respective brain area, [2] covered by thousands of thorny protrusions (dendritic spines), [3] possess high levels of dendritic NMDA conductances, and [4] experience sustained somatic depolarizations in vivo and in vitro (UP states). In all spiny neurons of the forebrain, adequate glutamatergic inputs generate dendritic plateau potentials (dendritic UP states) characterized by (i) fast rise, (ii) plateau phase lasting several hundred milliseconds and (iii) abrupt decline at the end of the plateau phase. The dendritic plateau potential propagates towards the cell body decrementally to induce a long-lasting (longer than 100 ms, most often 200 – 800 ms) steady depolarization (~20 mV amplitude), which resembles a neuronal UP state. Based on voltage-sensitive dye imaging, the plateau depolarization in the soma is precisely time-locked to the regenerative plateau potential taking place in the dendrite. The somatic plateau rises after the onset of the dendritic voltage transient and collapses with the breakdown of the dendritic plateau depolarization. We hypothesize that neuronal UP states in vivo reflect the occurrence of dendritic plateau potentials (dendritic UP states). We propose that the somatic voltage waveform during a neuronal UP state is determined by dendritic plateau potentials. A mammalian spiny neuron uses dendritic plateau potentials to detect and transform coherent network activity into a ubiquitous neuronal UP state. The biophysical properties of dendritic plateau potentials allow neurons to quickly attune to the ongoing network activity, as well as secure the stable amplitudes of successive UP states.

Experiment has demonstrated that summation of excitatory post-synaptic protientials (EPSPs) in dendrites is non-linear. The sum of multiple EPSPs can be larger than their arithmetic sum, a superlinear summation due to the opening of voltage-gated channels and similar to somatic spiking. The so-called dendritic spike. The sum of multiple of EPSPs can also be smaller than their arithmetic sum, because the synaptic current necessarily saturates at some point. While these observations are well-explained by biophysical models the impact of dendritic spikes on computation remains a matter of debate. One reason is that dendritic spikes may fail to make the neuron spike; similarly, dendritic saturations are sometime presented as a glitch which should be corrected by dendritic spikes. We will provide solid arguments against this claim and show that dendritic saturations as well as dendritic spikes enhance single neuron computation, even when they cannot directly make the neuron fire. To explore the computational impact of dendritic spikes and saturations, we are using a binary neuron model in conjunction with Boolean algebra. We demonstrate using these tools that a single dendritic non-linearity, either spiking or saturating, combined with somatic non-linearity, enables a neuron to compute linearly non-separable Boolean functions (lnBfs). These functions are impossible to compute when summation is linear and the exclusive OR is a famous example of lnBfs. Importantly, the implementation of these functions does not require the dendritic non-linearity to make the neuron spike. Next, We show that reduced and realistic biophysical models of the neuron are capable of computing lnBfs. Within these models and contrary to the binary model, the dendritic and somatic non-linearity are tightly coupled. Yet we show that these neuron models are capable of linearly non-separable computations.

At early stages of visual processing, receptive fields are typically described as subtending local regions of space and thus performing computations on a narrow spatial scale. Nevertheless, stimulation well outside of the classical receptive field can exert clear and significant effects on visual processing. Given the distances over which they occur, the retinal mechanisms responsible for these long-range effects would certainly require signal propagation via active membrane properties. Here the physiology of a wide-field amacrine cell-the wiry cell-in macaque monkey retina is explored, revealing receptive fields that represent a striking departure from the classic structure. A single wiry cell integrates signals over wide regions of retina, 5-10 times larger than the classic receptive fields of most retinal ganglion cells. Wiry cells integrate signals over space much more effectively than predicted from passive signal propagation, and spatial integration is strongly attenuated during blockade of NMDA spikes but integration is insensitive to blockade of NaV channels with TTX. Thus these cells appear well suited for contributing to the long-range interactions of visual signals that characterize many aspects of visual perception. [ABSTRACT FROM AUTHOR]

Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N-methyl-D-aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K+ current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials. [ABSTRACT FROM AUTHOR]

A computational model of a biochemical network underlying synaptic plasticity is combined with simulated on-going electrical activity in a model of a hippocampal pyramidal neuron to study the impact of synapse location and inhibition on synaptic plasticity. The simulated pyramidal neuron is activated by the realistic stimulation protocol of causal and anticausal spike pairings of presynaptic and postsynaptic action potentials in the presence and absence of spatially targeted inhibition provided by basket, bistratified and oriens-lacunosum moleculare (OLM) interneurons. The resulting Spike-timing-dependent plasticity (STDP) curves depend strongly on the number of pairing repetitions, the synapse location and the timing and strength of inhibition. [ABSTRACT FROM AUTHOR]

Spiny neurons of amygdala, striatum, and cerebral cortex share four interesting features: (1) they are the most abundant cell type within their respective brain area, (2) covered by thousands of thorny protrusions (dendritic spines), (3) possess high levels of dendritic NMDA conductances, and (4) experience sustained somatic depolarizations in vivo and in vitro (UP states). In all spiny neurons of the forebrain, adequate glutamatergic inputs generate dendritic plateau potentials (''dendritic UP states'') characterized by (i) fast rise, (ii) plateau phase lasting several hundred milliseconds, and (iii) abrupt decline at the end of the plateau phase. The dendritic plateau potential propagates toward the cell body decrementally to induce a long-lasting (longer than 100 ms, most often 200-800 ms) steady depolarization (∼20 mV amplitude), which resembles a neuronal UP state. Based on voltage-sensitive dye imaging, the plateau depolarization in the soma is precisely time-locked to the regenerative plateau potential taking place in the dendrite. The somatic plateau rises after the onset of the dendritic voltage transient and collapses with the breakdown of the dendritic plateau depolarization. We hypothesize that neuronal UP states in vivo reflect the occurrence of dendritic plateau potentials (dendritic UP states). We propose that the somatic voltage waveform during a neuronal UP state is determined by dendritic plateau potentials. A mammalian spiny neuron uses dendritic plateau potentials to detect and transform coherent network activity into a ubiquitous neuronal UP state. The biophysical properties of dendritic plateau potentials allow neurons to quickly attune to the ongoing network activity, as well as secure the stable amplitudes of successive UP states. [ABSTRACT FROM AUTHOR]

In pursuit of the goal to understand and eventually reproduce the diverse functions of the brain, a key challenge lies in reverse engineering the peculiar biology-based “technology” that underlies the brain's remarkable ability to process and store information. The basic building block of the nervous system is the nerve cell, or “neuron,” yet after more than 100 years of neurophysiological study and 60 years of modeling, the information processing functions of individual neurons, and the parameters that allow them to engage in so many different types of computation (sensory, motor, mnemonic, executive, etc.) remain poorly understood. In this paper, we review both historical and recent findings that have led to our current understanding of the analog spatial processing capabilities of dendrites, the major input structures of neurons, with a focus on the principal cell type of the neocortex and hippocampus, the pyramidal neuron (PN). We encapsulate our current understanding of PN dendritic integration in an abstract layered model whose spatially sensitive branch-subunits compute multidimensional sigmoidal functions. Unlike the 1-D sigmoids found in conventional neural network models, multidimensional sigmoids allow the cell to implement a rich spectrum of nonlinear modulation effects directly within their dendritic trees. [ABSTRACT FROM PUBLISHER]

Pyramidal neuron (PN) dendrites compartmentalize voltage signals and can generate local spikes, which has led to the proposal that their dendrites act as independent computational subunits within a multilayered processing scheme. However, when a PN is strongly activated, back-propagating action potentials (bAPs) sweeping outward from the soma synchronize dendritic membrane potentials many times per second. How PN dendrites maintain the independence of their voltage-dependent computations, despite these repeated voltage resets, remains unknown. Using a detailed compartmental model of a layer 5 PN, and an improved method for quantifying subunit independence that incorporates a more accurate model of dendritic integration, we first established that the output of each dendrite can be almost perfectly predicted by the intensity and spatial configuration of its own synaptic inputs, and is nearly invariant to the rate of bAP-mediated "cross-talk" from other dendrites over a 100-fold range. Then, through an analysis of conductance, voltage, and current waveforms within the model cell, we identify three biophysical mechanisms that together help make independent dendritic computation possible in a firing neuron, suggesting that a major subtype of neocortical neuron has been optimized for layered, compartmentalized processing under in-vivo-like spiking conditions. [ABSTRACT FROM AUTHOR]

Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly nonlinear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of loud sounds (i.e. strong glut. inputs) and amplify quiet sounds (i.e. glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP states have uniform amplitudes in a given neuron.

Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate, for a brief period of time. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly non linear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of "loud sounds" (i.e., strong glutamatergic inputs) and amplify "quiet sounds" (i.e., glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP states have uniform amplitudes in a given neuron. [ABSTRACT FROM AUTHOR]

The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between SWRs and hippocampal plasticity, little is known about how network state affects information processing in dendrites, the primary sites of synaptic input integration and plasticity. Here, we monitored somatic and basal dendritic activity in CA1 pyramidal cells in behaving mice using longitudinal two-photon calcium imaging integrated with simultaneous local field potential recordings. We found immobility was associated with an increase in dendritic activity concentrated during SWRs. Coincident dendritic and somatic activity during SWRs predicted increased coupling during subsequent exploration of a novel environment. In contrast, somatic-dendritic coupling and SWR recruitment varied with cells' tuning distance to reward location during a goal-learning task. Our results connect SWRs with the stabilization of information processing within CA1 neurons and suggest that these mechanisms may be dynamically biased by behavioral demands. • Basal dendrites of mouse CA1 pyramidal cells coactivate with the soma during SWRs • Activity during SWRs in novel environments predicts future soma-dendrite coupling • Dendritic tuning dissociates from somatic firing during spatial reward learning • Cells tuned far from reward show increased dendritic coactivity and SWR recruitment Rolotti et al. combine calcium imaging and electrophysiology to study somatic-dendritic dynamics across behavior and network states in mouse hippocampus. Sharp-wave ripples modulate dendritic activity, inducing long-term changes in soma-dendrite coupling. Reinforcement alters ripple recruitment and dissociates dendritic-somatic spatial tuning. Ripples may facilitate dendritic reorganization to stabilize hippocampal computations. [ABSTRACT FROM AUTHOR]

Activation of the climbing fiber input powerfully excites cerebellar Purkinje cells via hundreds of widespread dendritic synapses, triggering dendritic spikes as well as a characteristic high-frequency burst of somatic spikes known as the complex spike. To investigate the relationship between dendritic spikes and the spikelets within the somatic complex spike, and to evaluate the importance of the dendritic distribution of climbing fiber synapses, we made simultaneous somatic and dendritic patch-clamp recordings from Purkinje cells in cerebellar slices. Injection of large climbing fiber-like synaptic conductances at the soma using dynamic clamp was sufficient to reproduce the complex spike, independently of dendritic spikes, indicating that neither a dendritic synaptic distribution nor dendritic spikes are required. Furthermore, we found that dendritic spikes are not directly linked to spikelets in the complex spike, and that each dendritic spike is associated with only 0.24±0.09 extra somatic spikelets. Rather, we demonstrate that dendritic spikes regulate the pause in firing that follows the complex spike. Finally, using dual somatic and axonal recording, we show that all spikelets in the complex spike are axonally generated. Thus, complex spike generation proceeds relatively independently of dendritic spikes, reflecting the dual functional role of climbing fiber input: triggering plasticity at dendritic synapses and generating a distinct output signal in the axon. The encoding of dendritic spiking by the post-complex spike pause provides a novel computational function for dendritic spikes, which could serve to link these two roles at the level of the target neurons in the deep cerebellar nuclei. [ABSTRACT FROM AUTHOR]

Synaptic plasticity rules widely determine how cortical networks develop and store information. Using confocal imaging and dual site focal synaptic stimulation, we show that basal dendrites, which receive the majority of synapses innervating neocortical pyramidal neurons, contain two compartments with respect to plasticity rules. Synapses innervating the proximal basal tree are easily modified when paired with the global activity of the neuron. In contrast, synapses innervating the distal basal tree fail to change in response to global suprathreshold activity or local dendritic spikes. These synapses can undergo long-term potentiation under unusual conditions when local NMDA spikes, which evoke large calcium transients, are paired with a "gating molecule," BDNF. Moreover, these synapses use a new temporal plasticity rule, which is an order of magnitude longer than spike timing dependent plasticity and prefers reversed presynaptic/postsynaptic activation order. The newly described plasticity compartmentalization of basal dendrites expands the networks plasticity rules and may support different learning and developmental functions. [ABSTRACT FROM AUTHOR]

Understanding the relationship between dendritic excitability and synaptic plasticity is vital for determining how dendrites regulate the input–output function of the neuron. Dendritic calcium spikes have been associated with the induction of long-term changes in synaptic efficacy. Here we use direct recordings from cerebellar Purkinje cell dendrites to show that synaptically activated local dendritic calcium spikes are potent triggers of cannabinoid release, producing a profound and short-term reduction in synaptic efficacy at parallel fiber synapses. Enhancing dendritic excitability by modulating dendritic large-conductance calcium-activated potassium (BK) channels improves the spread of dendritic calcium spikes and enhances cannabinoid release at the expense of spatial specificity. Our findings reveal that dendritic calcium spikes provide a local and tunable coincidence detection mechanism that readjusts synaptic gain when synchronous activity reaches athreshold, andthey reveal atight link between the regulation of dendritic excitability and the induction of synaptic plasticity [ABSTRACT FROM AUTHOR]

The mammalian accessory olfactory system is critical for the detection and identification of pheromones and the representation of complex stimuli including sex, genetic relatedness, and individual identity. Mitral cells, the principal cells of the accessory olfactory bulb (AOB), receive monosynaptic input from the sensory periphery and already show highly specific response properties, firing selectively for combinations of genetic markers and gender-specific cues. Vomeronasal sensory neuron axons form synapses onto distal tuft-like branches of mitral cell primary dendrites. We have studied dendritic excitability and synaptic integration in AOB mitral cell dendrites, and we show that dendrites of accessory olfactory bulb mitral cells support action potential propagation and can fire regenerative spike-like events that are likely to contribute to the integration of inputs to these cells. These tuft spikes may be important for the specificity of AOB mitral cell responses. [ABSTRACT FROM AUTHOR]

Abstract: In spike-timing-dependent plasticity (STDP) the synapses are potentiated or depressed depending on the temporal order and temporal difference of the pre- and post-synaptic signals. We present a biophysical model of STDP which assumes that not only the timing, but also the shapes of these signals influence the synaptic modifications. The model is based on a Hebbian learning rule which correlates the NMDA synaptic conductance with the post-synaptic signal at synaptic location as the pre- and post-synaptic quantities. As compared to a previous paper [Saudargiene, A., Porr, B., Worgotter, F., 2004. How the shape of pre- and post-synaptic signals can influence stdp: a biophysical model. Neural Comp.], here we show that this rule reproduces the generic STDP weight change curve by using real neuronal input signals and combinations of more than two (pre- and post-synaptic) spikes. We demonstrate that the shape of the STDP curve strongly depends on the shape of the depolarising membrane potentials, which induces learning. As these potentials vary at different locations of the dendritic tree, model predicts that synaptic changes are location dependent. The model is extended to account for the patterns of more than two spikes of the pre- and post-synaptic cells. The results show that STDP weight change curve is also activity dependent. [Copyright &y& Elsevier]

The ability of cells to generate an appropriate spike output depends on a balance between membrane depolarizations and the repolarizing actions of K+ currents. The high-voltage-activated Kv3 class of K+ channels repolarizes Na+ spikes to maintain high frequencies of discharge. However, little is known of the ability for these K+ channels to shape Ca2+ spike discharge or their ability to regulate Ca2+ spike-dependent burst output. Here we identify the role of Kv3 K+ channels in the regulation of Na+ and Ca2+ spike discharge, as well as burst output, using somatic and dendritic recordings in rat cerebellar Purkinje cells. Kv3 currents pharmacologically isolated in outside-out somatic membrane patches accounted for ∼ 40% of the total K+ current, were very fast and high voltage activating, and required more than 1 s to fully inactivate. Kv3 currents were differentiated from other tetraethylammonium-sensitive currents to establish their role in Purkinje cells under physiological conditions with current-clamp recordings. Dual somatic-dendritic recordings indicated that Kv3 channels repolarize Na+ and Ca2+ spikes, enabling high-frequency discharge for both types of cell output. We further show that during burst output Kv3 channels act together with large-conductance Ca2+-activated K+ channels to ensure an effective coupling between Ca2+ and Na+ spike discharge by preventing Na+ spike inactivation. By contributing significantly to the repolarization of Na+ and especially Ca2+ spikes, our data reveal a novel function for Kv3 K+ channels in the maintenance of high-frequency burst output for cerebellar Purkinje cells. [ABSTRACT FROM AUTHOR]

Gamma frequencies of burst discharge (>40 Hz) have become recognized in select cortical and non-cortical regions as being important in feature extraction, neural synchrony and oscillatory discharge. Pyramidal cells of the electrosensory lateral line lobe (ELL) of Apteronotus leptorhynchus generate burst discharge in relation to specific features of sensory input in vivo that resemble those recognized as gamma frequency discharge when examined in vitro. We have shown that these bursts are generated by an entirely novel mechanism termed conditional backpropagation that involves an intermittent failure of dendritic Na+ spike conduction. Conditional backpropagation arises from a frequency-dependent broadening of dendritic spikes during repetitive discharge, and a mismatch between the refractory periods of somatic and dendritic spikes. A high threshold class of K+ channel, AptKv3.3, is expressed at high levels and distributed over the entire soma-dendritic axis of pyramidal cells. AptKv3.3 channels are shown to contribute to the repolarization of both somatic and dendritic spikes, with pharmacological blockade of dendritic Kv3 channels revealing an important role in controlling the threshold for burst discharge. The entire process of conditional backpropagation and burst output is successfully simulated using a new compartmental model of pyramidal cells that incorporates a cumulative inactivation of dendritic K+ channels during repetitive discharge. This work is important in demonstrating how the success of spike backpropagation can control the output of a principle sensory neuron, and how this process is regulated by the distribution and properties of voltage-dependent K+ channels. [Copyright &y& Elsevier]