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

Abstract

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.

Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction inShank3Bknockout mice

“…We first confirmed previous reports that Shank3B KO mice have impaired sociability as well as impaired social discrimination memory (Peca et al, 2011; Tao et al, 2022). We utilized a three- trial direct social interaction test, with each trial separated by 24 hr, in which mice were exposed to a novel mouse (Novel 1) in trial 1, re-exposed to the same mouse (Familiar) in trial 2, and exposed to a second novel mouse (Novel 2) in trial 3 (Figure 1A).…”

“…It remains possible that vCA1 SWRs might differ between WT and Shank3B KO mice but that the parameters of our recordings did not capture this effect. Along these lines, it is relevant to note that a recent study found diminished SWR amplitude in Shank3B KO compared to WT mice during the 2 hr rest period after social interaction, a time likely important for social memory consolidation (Tao et al, 2022). However, since the main difference we noted in social interaction between WT and Shank3B KO mice was with investigation of novel social stimuli, which does not involve memory consolidation or retrieval, it seems likely that this social novelty deficit is not dependent on differences in SWRs.…”

The complexity of ventral CA1 and its multiple functionalities

“…In Shank3 KO mice, reduced sociability has led to observed disruption of sharp‐wave ripples. Neurons activated during social behaviour underlying in the vCA1 were minor in Shank3 KO mice, which resulted in an inability to socially discriminate 53 …”

“…Neurons activated during social behaviour underlying in the vCA1 were minor in Shank3 KO mice, which resulted in an inability to socially discriminate. 53 Defining the synaptic bases related to social behaviour would provide an insight to understand psychiatric disorders such as schizophrenia or depression, as this phenotype is articulated in a mouse model of autism. 53 Among the hippocampal subregions, dysfunction in CA1 is specific to schizophrenia, whereas dysfunction in CA2/CA3 is attributed to schizophrenia and bipolar disorder.…”

“…53 Defining the synaptic bases related to social behaviour would provide an insight to understand psychiatric disorders such as schizophrenia or depression, as this phenotype is articulated in a mouse model of autism. 53 Among the hippocampal subregions, dysfunction in CA1 is specific to schizophrenia, whereas dysfunction in CA2/CA3 is attributed to schizophrenia and bipolar disorder. Given that the vCA1 has a strong projection to the mPFC and ventral subiculum (vSUB) which are both involved in schizophrenia it is a suitable region to study psychiatric disorder.…”