Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment.

The apical dendrites of many neurons contain proximal and distal compartments that receive synaptic inputs from different brain regions. These compartments also contain distinct complements of ion channels that enable the differential processing of their respective synaptic inputs, making them functionally distinct. At present, the molecular mechanisms that specify dendritic compartments are not well understood. Here, we report that the extracellular matrix protein Reelin, acting through its downstream, intracellular Dab1 and Src family tyrosine kinase signaling cascade, is essential for establishing and maintaining the molecular identity of the distal dendritic compartment of cortical pyramidal neurons. We find that Reelin signaling is required for the striking enrichment of HCN1 and GIRK1 channels in the distal tuft dendrites of both hippocampal CA1 and neocortical layer 5 pyramidal neurons, where the channels actively filter inputs targeted to these dendritic domains.

Gating movements and ion permeation in HCN4 pacemaker channels.

The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures sheds light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlights the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation. Our results contribute mechanistic understanding on HCN channel gating, cyclic nucleotide-dependent modulation, and ion permeation.

HCN1 hyperpolarization-activated cyclic nucleotide-gated channels enhance evoked GABA release from parvalbumin-positive interneurons.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the cationic Ih current in neurons and regulate the excitability of neuronal networks. The function of HCN channels depends, in part, on their subcellular localization. Of the four HCN isoforms (HCN1-4), HCN1 is strongly expressed in the dendrites of pyramidal neurons (PNs) in hippocampal area CA1 but also in presynaptic terminals of parvalbumin-positive interneurons (PV+ INs), which provide strong inhibitory control over hippocampal activity. Yet, little is known about how HCN1 channels in these cells regulate the evoked release of the inhibitory transmitter GABA from their axon terminals. Here, we used genetic, optogenetic, electrophysiological, and imaging techniques to investigate how the electrophysiological properties of PV+ INs are regulated by HCN1, including how HCN1 activity at presynaptic terminals regulates the release of GABA onto PNs in CA1. We found that application of HCN1 pharmacological blockers reduced the amplitude of the inhibitory postsynaptic potential recorded from CA1 PNs in response to selective optogenetic stimulation of PV+ INs. Homozygous HCN1 knockout mice also show reduced IPSCs in postsynaptic cells. Finally, two-photon imaging using genetically encoded fluorescent calcium indicators revealed that HCN1 blockers reduced the probability that an extracellular electrical stimulating pulse evoked a Ca2+ response in individual PV+ IN presynaptic boutons. Taken together, our results show that HCN1 channels in the axon terminals of PV+ interneurons facilitate GABAergic transmission in the hippocampal CA1 region.

Hippocampal CA2 sharp-wave ripples reactivate and promote social memory.

The consolidation of spatial memory depends on the reactivation ('replay') of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)-synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep1-8 and whose disruption impairs spatial memory3,5,6,8. Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus7,9, the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory-the ability of an animal to recognize and remember a member of the same species-focusing on CA2 because of its essential role in social memory10-12. We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory.

Reduced Cholecystokinin-Expressing Interneuron Input Contributes to Disinhibition of the Hippocampal CA2 Region in a Mouse Model of Temporal Lobe Epilepsy.

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK+) interneurons and a functional impairment of CCK+ interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model.SIGNIFICANCE STATEMENT Impaired synaptic inhibition in hippocampal circuits has been identified as a key feature that contributes to the emergence and propagation of seizure activity in human patients and animal models of temporal lobe epilepsy (TLE). Among the hippocampal subfields, the CA2 region is particularly resilient to seizure-associated neurodegeneration and has been suggested to play a key role in seizure activity in TLE. Here we report that perisomatic inhibition of CA2 pyramidal neurons mediated by cholecystokinin-expressing interneurons is selectively reduced in acute hippocampal slices from epileptic mice. Parvalbumin-expressing interneurons, in contrast, appear relatively conserved in epileptic mice. These findings advance our understanding of the cellular mechanisms underlying inhibitory disruption in hippocampal circuits in a mouse model of spontaneous recurring seizures.

A circuit from hippocampal CA2 to lateral septum disinhibits social aggression.

Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression.

Somatic Depolarization Enhances Hippocampal CA1 Dendritic Spike Propagation and Distal Input-Driven Synaptic Plasticity.

Synaptic inputs that target distal regions of neuronal dendrites can often generate local dendritic spikes that can amplify synaptic depolarization, induce synaptic plasticity, and enhance neuronal output. However, distal dendritic spikes are subject to significant attenuation by dendritic cable properties, and often produce only a weak subthreshold depolarization of the soma. Nonetheless, such spikes have been implicated in memory storage, sensory perception and place field formation. How can such a weak somatic response produce such powerful behavioral effects? Here, we use dual dendritic and somatic recordings in acute hippocampal slices of male mice to reveal that dendritic spike propagation, but not spike initiation, is strongly enhanced when the somatic resting potential is depolarized, likely as a result of increased inactivation of A-type K+ channels. Somatic depolarization also facilitates the induction of a form of dendritic spike driven heterosynaptic plasticity that enhances memory specificity. Thus, the effect of somatic membrane depolarization to enhance dendritic spike propagation and long-term synaptic plasticity is likely to play an important role in hippocampal-dependent spatial representations as well as learning and memory.SIGNIFICANCE STATEMENT Neurons receive synaptic input along their dendrites but produce action potential (AP) output at their soma. Signals arriving at the distal dendrites of pyramidal neurons (PNs) have little impact on the soma unless they combine to initiate a dendritic spike, which needs to propagate to the soma to trigger an AP. This study shows that small subthreshold depolarization of the soma powerfully enhances the propagation of dendritic spikes, through inactivation of dendritic A-type potassium channels. Enhanced dendritic spike propagation also markedly facilitates the induction of a form of plasticity driven by the distal synaptic inputs. Thus, small changes in somatic membrane potential, similar to those observed in vivo, act as a powerful gate of neuronal information transfer.

Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory.

The hippocampus contains a diverse array of inhibitory interneurons that gate information flow through local cortico-hippocampal circuits to regulate memory storage. Although most studies of interneurons have focused on their role in fast synaptic inhibition mediated by GABA release, different classes of interneurons express unique sets of neuropeptides, many of which have been shown to exert powerful effects on neuronal function and memory when applied pharmacologically. However, relatively little is known about whether and how release of endogenous neuropeptides from inhibitory cells contributes to their behavioral role in regulating memory formation. Here we report that vasoactive intestinal peptide (VIP)-expressing interneurons participate in social memory storage by enhancing information transfer from hippocampal CA3 pyramidal neurons to CA2 pyramidal neurons. Notably, this action depends on release of the neuropeptide enkephalin from VIP neurons, causing long-term depression of feedforward inhibition onto CA2 pyramidal cells. Moreover, VIP neuron activity in the CA2 region is increased selectively during exploration of a novel conspecific. Our findings, thus, enhance our appreciation of how GABAergic neurons can regulate synaptic plasticity and mnemonic behavior by demonstrating that such actions can be mediated by release of a specific neuropeptide, rather than through classic fast inhibitory transmission.

Frequency-Dependent Synaptic Dynamics Differentially Tune CA1 and CA2 Pyramidal Neuron Responses to Cortical Input.

Entorhinal cortex neurons make monosynaptic connections onto distal apical dendrites of CA1 and CA2 pyramidal neurons through the perforant path (PP) projection. Previous studies show that differences in dendritic properties and synaptic input density enable the PP inputs to produce a much stronger excitation of CA2 compared with CA1 pyramidal neurons. Here, using mice of both sexes, we report that the difference in PP efficacy varies substantially as a function of presynaptic firing rate. Although a single PP stimulus evokes a 5- to 6-fold greater EPSP in CA2 compared with CA1, a brief high-frequency train of PP stimuli evokes a strongly facilitating postsynaptic response in CA1, with relatively little change in CA2. Furthermore, we demonstrate that blockade of NMDARs significantly reduces strong temporal summation in CA1 but has little impact on that in CA2. As a result of the differences in the frequency- and NMDAR-dependent temporal summation, naturalistic patterns of presynaptic activity evoke CA1 and CA2 responses with distinct dynamics, differentially tuning CA1 and CA2 responses to bursts of presynaptic firing versus single presynaptic spikes, respectively.SIGNIFICANCE STATEMENT Recent studies have demonstrated that abundant entorhinal cortical innervation and efficient dendritic propagation enable hippocampal CA2 pyramidal neurons to produce robust excitation evoked by single cortical stimuli, compared with CA1. Here we uncovered, unexpectedly, that the difference in efficacy of cortical excitation varies substantially as a function of presynaptic firing rate. A burst of stimuli evokes a strongly facilitating response in CA1, but not in CA2. As a result, the postsynaptic response of CA1 and CA2 to presynaptic naturalistic firing displays contrasting temporal dynamics, which depends on the activation of NMDARs. Thus, whereas CA2 responds to single stimuli, CA1 is selectively recruited by bursts of cortical input.

Synaptic Organization of Anterior Olfactory Nucleus Inputs to Piriform Cortex.

Odors activate distributed ensembles of neurons within the piriform cortex, forming cortical representations of odor thought to be essential to olfactory learning and behaviors. This odor response is driven by direct input from the olfactory bulb, but is also shaped by a dense network of associative or intracortical inputs to piriform, which may enhance or constrain the cortical odor representation. With optogenetic techniques, it is possible to functionally isolate defined inputs to piriform cortex and assess their potential to activate or inhibit piriform pyramidal neurons. The anterior olfactory nucleus (AON) receives direct input from the olfactory bulb and sends an associative projection to piriform cortex that has potential roles in the state-dependent processing of olfactory behaviors. Here, we provide a detailed functional assessment of the AON afferents to piriform in male and female C57Bl/6J mice. We confirm that the AON forms glutamatergic excitatory synapses onto piriform pyramidal neurons; and while these inputs are not as strong as piriform recurrent collaterals, they are less constrained by disynaptic inhibition. Moreover, AON-to-piriform synapses contain a substantial NMDAR-mediated current that prolongs the synaptic response at depolarized potentials. These properties of limited inhibition and slow NMDAR-mediated currents result in strong temporal summation of AON inputs within piriform pyramidal neurons, and suggest that the AON could powerfully enhance activation of piriform neurons in response to odor.SIGNIFICANCE STATEMENT Odor information is transmitted from olfactory receptors to olfactory bulb, and then to piriform cortex, where ensembles of activated neurons form neural representations of the odor. While these ensembles are driven by primary bulbar afferents, and shaped by intracortical recurrent connections, the potential for another early olfactory area, the anterior olfactory nucleus (AON), to contribute to piriform activity is not known. Here, we use optogenetic circuit-mapping methods to demonstrate that AON inputs can significantly activate piriform neurons, as they are coupled to NMDAR currents and to relatively modest disynaptic inhibition. The AON may enhance the piriform odor response, encouraging further study to determine the states or behaviors through which AON potentiates the cortical response to odor.

Postsynaptic integrative properties of dorsal CA1 pyramidal neuron subpopulations.

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.

The hippocampal CA2 region is essential for social memory.

The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory--the ability of an animal to remember a conspecific--with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit.

The impact of a given neuronal pathway depends on the number of synapses it makes with its postsynaptic target, the strength of each individual synapse, and the integrative properties of the postsynaptic dendrites. Here we explore the cellular and synaptic mechanisms responsible for the differential excitatory drive from the entorhinal cortical pathway onto mouse CA2 compared with CA1 pyramidal neurons (PNs). Although both types of neurons receive direct input from entorhinal cortex onto their distal dendrites, these inputs produce a 5- to 6-fold larger EPSP at the soma of CA2 compared with CA1 PNs, which is sufficient to drive action potential output from CA2 but not CA1. Experimental and computational approaches reveal that dendritic propagation is more efficient in CA2 than CA1 as a result of differences in dendritic morphology and dendritic expression of the hyperpolarization-activated cation current (Ih). Furthermore, there are three times as many cortical inputs onto CA2 compared with CA1 PN distal dendrites. Using a computational model, we demonstrate that the differences in dendritic properties of CA2 compared with CA1 PNs are necessary to enable the CA2 PNs to generate their characteristically large EPSPs in response to their cortical inputs; in contrast, CA1 dendritic properties limit the size of the EPSPs they generate, even to a similar number of cortical inputs. Thus, the matching of dendritic integrative properties with the density of innervation is crucial for the differential processing of information from the direct cortical inputs by CA2 compared with CA1 PNs.SIGNIFICANCE STATEMENT Recent discoveries have shown that the long-neglected hippocampal CA2 region has distinct synaptic properties and plays a prominent role in social memory and schizophrenia. This study addresses the puzzling finding that the direct entorhinal cortical inputs to hippocampus, which target the very distal pyramidal neuron dendrites, provide an unusually strong excitatory drive at the soma of CA2 pyramidal neurons, with EPSPs that are 5-6 times larger than those in CA1 pyramidal neurons. We here elucidate synaptic and dendritic mechanisms that account quantitatively for the marked difference in EPSP size. Our findings further demonstrate the general importance of fine-tuning the integrative properties of neuronal dendrites to their density of synaptic innervation.

Homologue structure of the SLAC1 anion channel for closing stomata in leaves.

The plant SLAC1 anion channel controls turgor pressure in the aperture-defining guard cells of plant stomata, thereby regulating the exchange of water vapour and photosynthetic gases in response to environmental signals such as drought or high levels of carbon dioxide. Here we determine the crystal structure of a bacterial homologue (Haemophilus influenzae) of SLAC1 at 1.20 Å resolution, and use structure-inspired mutagenesis to analyse the conductance properties of SLAC1 channels. SLAC1 is a symmetrical trimer composed from quasi-symmetrical subunits, each having ten transmembrane helices arranged from helical hairpin pairs to form a central five-helix transmembrane pore that is gated by an extremely conserved phenylalanine residue. Conformational features indicate a mechanism for control of gating by kinase activation, and electrostatic features of the pore coupled with electrophysiological characteristics indicate that selectivity among different anions is largely a function of the energetic cost of ion dehydration.

Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function.

In many cortical neurons, HCN1 channels are the major contributors to Ih, the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of Ih in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of Ih decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or Ih blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question.

Modulation of aggression by social novelty recognition memory in the hippocampal CA2 region.

The dorsal CA2 subregion (dCA2) of the hippocampus exerts a critical role in social novelty recognition (SNR) memory and in the promotion of social aggression. Whether the social aggression and SNR memory functions of dCA2 are related or represent independent processes is unknown. Here we investigated the hypotheses that an animal is more likely to attack a novel compared to familiar animal and that dCA2 promotes social aggression through its ability to discriminate between novel and familiar conspecifics. To test these ideas, we conducted a multi-day resident intruder (R-I) test of aggression towards novel and familiar conspecifics. We found that mice were more likely to attack a novel compared to familiarized intruder and that silencing of dCA2 caused a more profound inhibition of aggression towards a novel than familiarized intruder. To explore whether and how dCA2 pyramidal neurons encode aggression, we recorded their activity using microendoscopic calcium imaging throughout the days of the R-I test. We found that a fraction of dCA2 neurons were selectively activated or inhibited during exploration, dominance, and attack behaviors and that these signals were enhanced during interaction with a novel compared to familiarized conspecific. Based on dCA2 population activity, a set of binary linear classifiers accurately decoded whether an animal was engaged in each of these forms of social behavior. Of particular interest, the accuracy of decoding aggression was greater with novel compared to familiarized intruders, with significant cross-day decoding using the same familiar animal on each day but not for a familiar-novel pair. Together, these findings demonstrate that dCA2 integrates information about social novelty with signals of behavioral state to promote aggression towards novel conspecifics.

Tuned geometries of hippocampal representations meet the computational demands of social memory.

Social memory consists of two processes: the detection of familiar compared with novel conspecifics and the detailed recollection of past social episodes. We investigated the neural bases for these processes using calcium imaging of dorsal CA2 hippocampal pyramidal neurons, known to be important for social memory, during social/spatial encounters with novel conspecifics and familiar littermates. Whereas novel individuals were represented in a low-dimensional geometry that allows for generalization of social identity across different spatial locations and of location across different identities, littermates were represented in a higher-dimensional geometry that supports high-capacity memory storage. Moreover, familiarity was represented in an abstract format, independent of individual identity. The degree to which familiarity increased the dimensionality of CA2 representations for individual mice predicted their performance in a social novelty recognition memory test. Thus, by tuning the geometry of structured neural activity, CA2 is able to meet the demands of distinct social memory processes.

Regulation by Presynaptic NMDA Receptors of Non-Linear Postsynaptic Summation of the Cortical Input to CA1 Pyramidal Neurons.

Entorhinal cortex (EC) LIII and LII glutamatergic neurons make monosynaptic connections onto distal apical dendrites of hippocampal CA1 and CA2 pyramidal neurons (PNs), respectively, through perforant path (PP) projections. We previously reported that a brief train of PP stimuli evokes strong supralinear temporal summation of excitatory postsynaptic potentials (EPSPs) in CA1 PNs that requires NMDAR activation, with relatively little summation in CA2 PNs in mice of either sex. Here we provide evidence from combined immunogold electron microscopy, cell-type specific genetic deletion and pharmacology that the NMDARs required for supralinear temporal summation of the CA1 PP EPSP are presynaptic, located in the PP terminals. Moreover, we found that the number of NMDARs in PP terminals innervating CA1 PNs is significantly greater than that found in PP terminals innervating CA2 PNs, providing a potential explanation for the difference in temporal summation in these two classes of hippocampal PNs.

Social odor discrimination and its enhancement by associative learning in the hippocampal CA2 region.

Although the hippocampus is crucial for social memory, how social sensory information is combined with contextual information to form episodic social memories remains unknown. Here, we investigated the mechanisms for social sensory information processing using two-photon calcium imaging from hippocampal CA2 pyramidal neurons (PNs)-which are crucial for social memory-in awake head-fixed mice exposed to social and non-social odors. We found that CA2 PNs represent social odors of individual conspecifics and that these representations are refined during associative social odor-reward learning to enhance the discrimination of rewarded compared with unrewarded odors. Moreover, the structure of the CA2 PN population activity enables CA2 to generalize along categories of rewarded versus unrewarded and social versus non-social odor stimuli. Finally, we found that CA2 is important for learning social but not non-social odor-reward associations. These properties of CA2 odor representations provide a likely substrate for the encoding of episodic social memory.

A neural mechanism for discriminating social threat from social safety.

The ability to distinguish a threatening from non-threatening conspecific based on past experience is critical for adaptive social behaviors. Although recent progress has been made in identifying the neural circuits that contribute to different types of positive and negative social interactions, the neural mechanisms that enable the discrimination of individuals based on past aversive experiences remain unknown. Here, we developed a modified social fear conditioning paradigm that induced in both sexes robust behavioral discrimination of a conspecific associated with a footshock (CS+) from a non-reinforced interaction partner (CS-). Strikingly, chemogenetic or optogenetic silencing of hippocampal CA2 pyramidal neurons, which have been previously implicated in social novelty recognition memory, resulted in generalized avoidance fear behavior towards the equally familiar CS-and CS+. One-photon calcium imaging revealed that the accuracy with which CA2 representations discriminate the CS+ from the CS-animal was enhanced following social fear conditioning and strongly correlated with behavioral discrimination. Moreover the CA2 representations incorporated a generalized or abstract representation of social valence irrespective of conspecific identity and location. Thus, our results demonstrate, for the first time, that the same hippocampal CA2 subregion mediates social memories based on conspecific familiarity and social threat, through the incorporation of a representation of social valence into an initial representation of social identity.