Long-term social isolation inhibits autophagy activation, induces postsynaptic dysfunctions and impairs spatial memory.

Social isolation in adolescence leads to lasting deficits in hippocampal-dependent tasks. The reported effects of isolation on learning and memory in the Morris water maze and synaptic-related proteins have been inconsistent. Moreover, the autophagy level and its effect on cognition in the isolation model are also not clear. In the present study, we did an extended isolation period up to six months to establish a stable and appropriate isolation model to investigate the cognitive changes associated with it. The mTOR inhibitor rapamycin was systemically administered to mice to determine the roles of autophagy activation on cognitive changes. We discovered that long-term post-weaning social isolation (L-PWSI) produced marked deficits in spatial learning and memory and inhibited CA1 long-term potentiation (LTP), but paired-pulse facilitation (PPF) and input/output (I/O) curve were unaffected. The results further showed that the L-PWSI significantly decreased the protein expression levels of PSD-95, GluA1, NR1 and NR2B in the hippocampus, and no significant changes in the extracellular release of glutamate and the protein expression levels of synaptophysin, synapsin I, GAP-43, NR2A and GABAA. Moreover, we found that L-PWSI increased the protein expression of p-AKT/AKT, p-mTOR/mTOR and p62, whereas the protein levels of LC3B and Beclin1 were decreased indicating an inhibition in autophagy activity. Intraperitoneal injection of rapamycin significantly potentiated fEPSP slope and cognition-related proteins expression in the L-PWSI mice. These results therefore suggest that L-PWSI induces postsynaptic dysfunction by disrupting the interaction between AMPAR, NMDAR and PSD-95, and inhibit the autophagy activity which led to impaired spatial memory and cognitive function.