Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice.

The ability to remember conspecifics is critical for adaptive cognitive functioning and social communication, and impairments of this ability are hallmarks of autism spectrum disorders (ASDs). Although hippocampal ventral CA1 (vCA1) neurons are known to store social memories, how their activities are coordinated remains unclear. Here we show that vCA1 social memory neurons, characterized by enhanced activity in response to memorized individuals, were preferentially reactivated during sharp-wave ripples (SPW-Rs). Spike sequences of these social replays reflected the temporal orders of neuronal activities within theta cycles during social experiences. In ASD model Shank3 knockout mice, the proportion of social memory neurons was reduced, and neuronal ensemble spike sequences during SPW-Rs were disrupted, which correlated with impaired discriminatory social behavior. These results suggest that SPW-R-mediated sequential reactivation of neuronal ensembles is a canonical mechanism for coordinating hippocampus-dependent social memories and its disruption underlie the pathophysiology of social memory defects associated with ASD.

Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex.

For efficient cortical processing, neural circuit dynamics must be spatially and temporally regulated with great precision. Although parvalbumin-positive (PV) interneurons can control network synchrony, it remains unclear how they contribute to spatio-temporal patterning of activity. We investigated this by optogenetic inactivation of PV cells with simultaneous two-photon Ca2+ imaging from populations of neurons in mouse visual cortex in vivo. For both spontaneous and visually evoked activity, PV interneuron inactivation decreased network synchrony. But, interestingly, the response reliability and spatial extent of coactive neuronal ensembles during visual stimulation were also disrupted by PV-cell suppression, which reduced the functional repertoire of ensembles. Thus, PV interneurons can control the spatio-temporal dynamics of multineuronal activity by functionally sculpting neuronal ensembles and making them more different from each other. In doing so, inhibitory circuits could help to orthogonalize multicellular patterns of activity, enabling neural circuits to more efficiently occupy a higher dimensional space of potential dynamics.

Interpyramid spike transmission stabilizes the sparseness of recurrent network activity.

Cortical synaptic strengths vary substantially from synapse to synapse and exhibit a skewed distribution with a small fraction of synapses generating extremely large depolarizations. Using multiple whole-cell recordings from rat hippocampal CA3 pyramidal cells, we found that the amplitude of unitary excitatory postsynaptic conductances approximates a lognormal distribution and that in the presence of synaptic background noise, the strongest fraction of synapses could trigger action potentials in postsynaptic neurons even with single presynaptic action potentials, a phenomenon termed interpyramid spike transmission (IpST). The IpST probability reached 80%, depending on the network state. To examine how IpST impacts network dynamics, we simulated a recurrent neural network embedded with a few potent synapses. This network, unlike many classical neural networks, exhibited distinctive behaviors resembling cortical network activity in vivo. These behaviors included the following: 1) infrequent ongoing activity, 2) firing rates of individual neurons approximating a lognormal distribution, 3) asynchronous spikes among neurons, 4) net balance between excitation and inhibition, 5) network activity patterns that was robust against external perturbation, 6) responsiveness even to a single spike of a single excitatory neuron, and 7) precise firing sequences. Thus, IpST captures a surprising number of recent experimental findings in vivo. We propose that an unequally biased distribution with a few select strong synapses helps stabilize sparse neuronal activity, thereby reducing the total spiking cost, enhancing the circuit responsiveness, and ensuring reliable information transfer.

Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice.

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

Ventromedial prefrontal neurons represent self-states shaped by vicarious fear in male mice.

Perception of fear induced by others in danger elicits complex vicarious fear responses and behavioral outputs. In rodents, observing a conspecific receive aversive stimuli leads to escape and freezing behavior. It remains unclear how these behavioral self-states in response to others in fear are neurophysiologically represented. Here, we assess such representations in the ventromedial prefrontal cortex (vmPFC), an essential site for empathy, in an observational fear (OF) paradigm in male mice. We classify the observer mouse's stereotypic behaviors during OF using a machine-learning approach. Optogenetic inhibition of the vmPFC specifically disrupts OF-induced escape behavior. In vivo Ca2+ imaging reveals that vmPFC neural populations represent intermingled information of other- and self-states. Distinct subpopulations are activated and suppressed by others' fear responses, simultaneously representing self-freezing states. This mixed selectivity requires inputs from the anterior cingulate cortex and the basolateral amygdala to regulate OF-induced escape behavior.

Distinct functions of ventral CA1 and dorsal CA2 in social memory.

PURPOSE OF REVIEW: For animals that live in social groups, the ability to recognize conspecifics is essential. Recent studies of both human patients and animal models have vigorously sought to discern the precise mechanisms by which hippocampal neurons and neural circuits contribute to the encoding, consolidation, storage, and retrieval of social memory. In particular, optogenetic manipulation enables us to investigate the presence of memory engrams. RECENT FINDINGS: We recently revealed the presence of social memory engrams in hippocampal ventral CA1 neurons, using optogenetic manipulation and calcium (Ca2+) imaging. SUMMARY: In the present manuscript, we discuss the current viewpoints on two hippocampal subregions in regards to social memory representation, namely dorsal CA2 for information processing and ventral CA1 for the storage of social memory, specifically from the perspectives of behavioral neuroscience and neurophysiology.

AMP-activated protein kinase mediates activity-dependent axon branching by recruiting mitochondria to axon.

During development, axons are guided to their target areas and provide local branching. Spatiotemporal regulation of axon branching is crucial for the establishment of functional connections between appropriate pre- and postsynaptic neurons. Common understanding has been that neuronal activity contributes to the proper axon branching; however, intracellular mechanisms that underlie activity-dependent axon branching remain elusive. Here, we show, using primary cultures of the dentate granule cells, that neuronal depolarization-induced rebalance of mitochondrial motility between anterograde versus retrograde transport underlies the proper formation of axonal branches. We found that the depolarization-induced branch formation was blocked by the uncoupler p-trifluoromethoxyphenylhydrazone, which suggests that mitochondria-derived ATP mediates the observed phenomena. Real-time analysis of mitochondrial movement defined the molecular mechanisms by showing that the pharmacological activation of AMP-activated protein kinase (AMPK) after depolarization increased anterograde transport of mitochondria into axons. Simultaneous imaging of axonal morphology and mitochondrial distribution revealed that mitochondrial localization preceded the emergence of axonal branches. Moreover, the higher probability of mitochondrial localization was correlated with the longer lifetime of axon branches. We qualitatively confirmed that neuronal ATP levels decreased immediately after depolarization and found that the phosphorylated form of AMPK was increased. Thus, this study identifies a novel role for AMPK in the transport of axonal mitochondria that underlie the neuronal activity-dependent formation of axon branches.

Unbalanced excitability underlies offline reactivation of behaviorally activated neurons.

Hippocampal sharp waves (SWs)/ripples represent the reactivation of neurons involved in recently acquired memory and are crucial for memory consolidation. By labeling active cells with fluorescent protein under the control of an immediate-early gene promoter, we found that neurons that had been activated while mice explored a novel environment were preferentially reactivated during spontaneous SWs in hippocampal slices in vitro. During SWs, the reactivated neurons received strong excitatory synaptic inputs as opposed to a globally tuned network balance between excitation and inhibition.

GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.

Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.