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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) sleep 1 – 8 and whose disruption impairs spatial memory 3 , 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 hippocampus 7 , 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 memory 10 – 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. Social memory is consolidated in the brain through the reactivation of neuronal firing by sharp-wave ripples in the CA2 region of the hippocampus, in a similar way to the consolidation of spatial memory.

Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory. Although the CA2 region of the hippocampus has been implicated in social memory, its precise role has been unclear. Here, the authors show that the dorsal subregion of CA2 is required for the encoding, consolidation and recall of social memory through a circuit linking it to ventral CA1.

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. Pyramidal neurons in the hippocampal CA2 region in mice promote social aggression via a disinhibitory circuit involving the lateral septum and ventromedial hypothalamus.

The hippocampal CA2 region is essential for social memory. To determine whether CA2 activity encodes social interactions, we recorded extracellularly from CA2 pyramidal neurons (PNs) in male mice during social behavior. Although CA2 neuronal firing showed only weak spatial selectivity, it accurately encoded contextual changes and distinguished between a novel and a familiar mouse. In the Df(16)A+/− mouse model of the human 22q11.2 microdeletion, which confers a 30-fold increased risk of schizophrenia, CA2 social coding was impaired, consistent with the social memory deficit observed in these mice; in contrast, spatial coding accuracy was greatly enhanced. CA2 PNs were previously found to be hyperpolarized in Df(16)A+/− mice, likely due to upregulation of TREK-1 K+ current. We found that TREK-1 blockade rescued social memory and CA2 social coding in Df(16)A+/− mice, supporting a crucial role for CA2 in the normal encoding of social stimuli and in social behavioral dysfunction in disease.Donegan et al. show that hippocampal CA2 neurons contribute to social memory by encoding social novelty. Abnormal CA2 coding and social memory in a mouse model of the 22q11.2 microdeletion are rescued by blocking elevated CA2 TREK-1 K+ current.

In addition to providing well-characterized excitatory inputs, the entorhinal cortex also sends long-range inhibitory projections to the hippocampus. Basu et al. described this input in detail and characterized its role for learning and memory. Multimodal sensory stimuli activate long-range inhibitory input in vivo. This input enables precisely timed information transfer within the cortico-hippocampal circuit. In this way, long-range inhibitory projections play an important role in providing specificity of fear conditioning, and thus help prevent overgeneralization. Science , this issue p. 10.1126/science.aaa5694 Inhibitory inputs from the lateral entorhinal cortex help to make contextual memory associations specific. The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these γ-aminobutyric acid (GABA)–releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based long-term memory associations by assessing the salience of mnemonic information to the immediate sensory input.

▪ Abstract  Hyperpolarization-activated cation currents, termed I f , I h , or I q , were initially discovered in heart and nerve cells over 20 years ago. These currents contribute to a wide range of physiological functions, including cardiac and neuronal pacemaker activity, the setting of resting potentials, input conductance and length constants, and dendritic integration. The hyperpolarization-activated, cation nonselective (HCN) gene family encodes the channels that underlie I h . Here we review the relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native I h in neurons and cardiac muscle. Moreover, we consider selected examples of the expanding physiological functions of I h with a view toward understanding how the properties of HCN channels contribute to these diverse functional roles.

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. Cells called neurons carry information—in the form of electrical signals—around the brain. These cells connect to each other in complex networks and each neuron is able to form junctions, or synapses, with many neighbors. In a neuron, small electrical signals start from synapses at the tips of branched structures called dendrites. From there, these signals travel to the cell body of the neuron to activate a larger electrical signal—called an action potential—that travels along a long tail-like extension, called the axon, to reach synapses with other neurons. In the dendrites, the small electrical signals can be amplified by rapid changes in the concentration of sodium ions, known as Na+ spikes. Although they were first recorded over 40 years ago, it is not clear how important the Na+ spikes are for triggering action potentials. In this study, Sun et al. studied a type of neuron in the hippocampus called CA2 pyramidal neurons, which are involved in social memory and aggression. Unlike most other neurons in this region, CA2 neurons are strongly activated by signals from a neighboring region of the brain called the entorhinal cortex. The experiments show that Na+ spikes are able to travel from the dendrites to the cell body of these neurons, where they are required to trigger action potentials. However, this is not the case for other neurons in the hippocampus, where the Na+ spikes are very weak by the time they reach the cell body. Sun et al. used a computational modeling technique to compare the different types of neurons in the hippocampus. The dendrites of these cells have different branching patterns and shapes, and the model suggests that this may explain the differences in how well the Na+ spikes travel to the cell body. The next major challenge is to understand the role of the Na+ spikes in social memory and other complex behaviors that are controlled by CA2 neurons.

CA2 neuron inactivation leads to a severe deficit in social memory, while having little effect on other well-known hippocampal functions such as contextual or spatial memory. Social memory in the hippocampus While years of research have assigned a variety of functions to the CA1 and CA3 areas of the hippocampus, the role of the smaller CA2 region has remained obscure. Here, using a transgenic mouse that allows for specific manipulations of CA2 hippocampal neurons, Frederick Hitti and Steven Siegelbaum map the specific cortical inputs to the CA2 region and determine that CA2 neuron inactivation can lead to a severe deficit in social memory, while having no effects on other well-known hippocampal functions such as contextual or spatial memory. The authors speculate that deficits in CA2 function may contribute to the social problems of individuals with autism or schizophrenia. The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when 1 . 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 2 . 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 7 . 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 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. Structure of stomatal anion channel SLAC1 SLAC1 is a recently identified anion channel found in the leaves of plants, where it controls turgor pressure and stomatal opening in response to environmental factors including carbon dioxide, ozone and drought. The X-ray crystal structure of a bacterial homologue of SLAC1 — the tellurite resistance protein TehA from Haemophilus influenzae — has now been determined. Structure-inspired mutagenesis was used to analyse the conductance properties of the channel. Electrostatic features of the pore suggest that selectivity among different anions is largely a function of the energetic cost of ion dehydration. This work, together with further studies of the function of the bacterial protein, suggests that SLAC1 and TehA represent a large family of selective anion channels controlled by environmental stimuli. SLAC1 is a plant ion channel that controls turgor pressure in the guard cells of plant stomata, thereby regulating the exchange of water vapour and photosynthetic gases in response to environmental signals. Here, the X-ray crystal structure of a bacterial homologue of SLAC1 has been solved, and structure-inspired mutagenesis has been used to analyse the conductance properties of the channel. The findings indicate that selectivity among different anions is largely a function of the energetic cost of ion dehydration.

De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo sequence variations in the human HCN1 voltage-gated channel gene, p.G391D and p.M153I ( Hcn1 G380D/+ and Hcn1 M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic–clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na + channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an impairment in inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the necessity of tailoring effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool toward reaching this objective.