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.

Summary Although the hippocampus is known to be important for declarative memory, how hippocampal output regulates motivated behaviors, such as social aggression, is less well understood. Here we report that hippocampal CA2 pyramidal neurons, which are important for social memory, promote social aggression. This action depends on CA2 output to the lateral septum that is selectively enhanced immediately prior to attack. Activation of lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventro-medial hypothalamus known to trigger attack. The social hormone arginine-vasopressin enhances social aggression by acting on arginine-vasopressin 1b receptors on CA2 presynaptic terminals in lateral septum to facilitate excitatory synaptic transmission. In this manner, release of vasopressin in 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 or proceeds to promote motivated social aggression.

expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. J Neurophysiol 109: 1940 -1953, 2013. First published January 16, 2013 doi:10.1152/jn.00010.2013The rodent hippocampus can be divided into dorsal (DHC) and ventral (VHC) domains on the basis of behavioral, anatomical, and biochemical differences. Recently, we reported that CA1 pyramidal neurons from the VHC were intrinsically more excitable than DHC neurons, but the specific ionic conductances contributing to this difference were not determined. Here we investigated the hyperpolarizationactivated current (I h ) and the expression of HCN1 and HCN2 channel subunits in CA1 pyramidal neurons from the DHC and VHC. Measurement of I h with cell-attached patches revealed a significant depolarizing shift in the V 1/2 of activation for dendritic h-channels in VHC neurons (but not DHC neurons), and ultrastructural immunolocalization of HCN1 and HCN2 channels revealed a significantly larger HCN1-to-HCN2 ratio for VHC neurons (but not DHC neurons). These observations suggest that a shift in the expression of HCN1 and HCN2 channels drives functional changes in I h for VHC neurons (but not DHC neurons) and could thereby significantly alter the capacity for dendritic integration of these neurons. CA1 pyramidal neuron; dorsal hippocampus; ventral hippocampus; hyperpolarization-activated current; HCN channel THE RODENT HIPPOCAMPUS can be divided along its longitudinal (septotemporal) axis into dorsal (the dorsal hippocampus, or DHC) and ventral (the ventral hippocampus, or VHC) components on the basis of behavioral, anatomical, and biochemical differences between these two domains (Bannerman et al.

Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29 -32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K ϩ channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K ϩ channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state.

Alzheimer’s disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.