Deconstruction of the retrosplenial granular cortex for social behavior in the mouse model of fragile X syndrome

Abstract

Deficits in fragile X mental retardation 1 protein lead to fragile X syndrome (FXS) with mental retardation and social activity disorder. Until now, the neuronal circuits that mediate the social impairments of FXS were mostly unclear. Accidently, we found fewer c-fos expression in RSG of KO than WT mice after social behavior test. Inactivation of RSG neurons decreased social novelty but not the sociability of naive mice. Interestingly, although the RSG neurons of KO mice had higher background activity, fewer social contact-related Ca2+ neurons were observed during social interaction test via one-photon Ca2+ imaging in freely-behaving mice. Strikingly, enhancing the activity of RSG neurons rescued the abnormal social novelty in KO mice. Further studies proved that the innervations from the subiculum and ACC to RSG contributes to the social behavior. Take together, we found that abnormal activity in the retrosplenial granular cortex (RSG) led to social novelty deficits in Fmr1-knockout (KO) mice. Moreover, selective manipulation of RSG neurons may be an effective strategy to treat the social deficits in FXS.One Sentence SummaryDeletion of FMRP leads to lower social-related neuronal activity in the RSG; this causes social novelty deficits in Fmr1-KO mice.

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

“…These data indicate that SENP1 is a candidate gene for ''ASD predominant gene'' affecting primarily social functions and the RSA region may serve as a circuitry node implicated in regulating mammalian social behaviors. Interestingly, it is recently reported that retrosplenial granular cortex (RSG) is also responsible for social behavior deficits of Fmr1 knockout mice (Shang et al, 2021). Together, these findings support the notion that the retrosplenial cortex plays a critical role in regulating social behaviors of mice.…”

Inhibitory inputs from hippocampal CA1 to retrosplenial agranular cortex gate social behavior

“…The work by Vesuna et al showed that abnormal elevated neural activity in RSC of mice caused by ketamine treatment led to dissociated behaviors including defects in social interaction in an interesting dose-dependent manner, which strongly implied that neural activity in RSC may play a critical role in salience processing for social interaction of animals (Vesuna et al, 2020). Together with our work and others, we showed that the synaptic transmission in RSC neurons were clearly disrupted in several ASD mice models including Senp1 +/and Fmr1 -/y mice (Shang et al, 2021;Yang et al, 2021). In this work, we proposed a model in which the inhibitory projection from PV-positive neurons of CA1 to RSA serves as a salience processing node to filter out non-social information flowing through RSA from sensory cortices.…”

“…Moreover, we found that neural activity was abnormally upregulated in RSC of MECP2 overexpressed mouse and functional connectivity of RSC associated with other brain regions were increased in the brain of non-human primate models for ASD, comparing to wild-type (WT) animals (Cai et al, 2020;Yu et al, 2020). Furthermore, our group, together with Li and colleagues, found that excitatory and inhibitory synaptic transmission in RSC are significantly altered in various genetic mouse models of ASD (Shang et al, 2021;Yang et al, 2021). Accumulated evidences suggest that RSC is implicated in regulating social behavior.…”