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

Abstract

Social memory dysfunction is a feature of several neuropsychiatric and neurodevelopmental disorders. Mutation or deletion of the SHANK3 gene, which codes for a synaptic scaffolding protein, has been linked to autism spectrum disorder (ASD) and Phelan-McDermid syndrome, conditions associated with impairments in social memory. Shank3B knockout (KO) mice exhibit several behavioral abnormalities that may be analogous to symptoms of ASD, including social discrimination deficits. The CA2 region of the hippocampus integrates numerous afferents and sends a major output to the ventral CA1 (vCA1), circuitry that plays an important role in social memory. Despite finding few differences in excitatory afferents to the CA2 in Shank3B KO mice, chemogenetic activation of CA2 excitatory neurons restored social recognition function to wildtype (WT) levels. Specific activation of the CA2-vCA1 circuitry had a similar effect. Neuronal oscillations in the theta, gamma and, sharp wave ripple ranges have been linked to social memory, but we observed no differences in these measures between WT and Shank3B KO mice in the vCA1 in response to social stimuli. However, activation of CA2 excitatory neurons enhanced vCA1 theta power in Shank3B KO mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can be sufficient to invoke latent function, particularly with respect to social memory dysfunction. The extent to which vCA1 network oscillations in the theta range are responsible for rescued behavioral function remains unknown.

A Novel Head-Fixed Assay for Social Touch in Mice Uncovers Aversive Responses in Two Autism Models

“…Some autistic individuals have difficulty recognizing and recalling faces of strangers (Williams et al, 2005;Stantić et al, 2022). Similarly, the Shank3B model of ASD shows deficits in discriminating between a novel and a familiar mouse (Cope et al, 2023). In our social touch assay, we observed that Fmr1 KO mice (n=8-10) exhibit similar levels of aversion to forced social touch with a familiar mouse and a stranger mouse (same-sex) (Fig.…”

“…Finally, we observed ASD mice display similar levels of avoidance and AFEs in response to forced social touch from a familiar mouse relative to a stranger mouse. This finding was not unusual given that both ASD individuals and mouse models display deficits in social memory (Williams et al, 2005;Stantić et al, 2022;Cope et al, 2023).…”

Prosapip1 in the dorsal hippocampus mediates synaptic protein composition, long-term potentiation, and spatial memory

“…The novelty T-maze focuses on both spatial learning and memory, and with its short, 1-minute inter-trial interval, this procedure is examining spatial working memory (Sharma et al, 2010; d’Isa et al, 2021). The 3-chamber social interaction test is assessing baseline sociability and also social recognition memory (Meira et al, 2018; Tzakis and Holahan, 2019; Wang and Zhan, 2022; Cope et al, 2023; Wei et al, 2024). Finally, the Barnes maze tests both spatial learning and working memory in intra-day trials, while simultaneously testing long-term contextual and spatial memory in inter-day trials and the probe test (Bach et al, 1995; Sharma et al, 2010; Rosenfeld and Ferguson, 2014; Pitts, 2018).…”

“…Loss of Prosapip1 in CA1 is likely leading to decreased performance in the novel object recognition, novelty T-maze, and Barnes maze tests. The lack of social recognition displayed by Prosapip1(flx/flx);Syn1-Cre(+) mice and AAV-Cre-infected mice is likely attributed to the loss of Prosapip1 in the CA2 subregion of the dHP, which is the primary subregion controlling social recognition memory (Meira et al, 2018; Tzakis and Holahan, 2019; Wang and Zhan, 2022; Cope et al, 2023; Wei et al, 2024). Specifically, silencing the CA2 subregion of the dHP impairs social memory formation and consolidation (Meira et al, 2018).…”