Oxytocin agonist TGOT differentially modulates synaptic plasticity and intrinsic excitability in a sex-specific manner in the juvenile rat hippocampus

Oxytocin (OXT) regulates social behavior and cognition in the mammalian brain through its receptor, OXTR, which is widely expressed, including in the hippocampus. OXTR expression changes across development in a sex-dependent manner. We recently showed that blocking OXTR in hippocampal CA1 impairs long-term object location memory (OLM) in juvenile male rats. Here, we examine the effect of OXT in juvenile males and females using in vivo and ex vivo electrophysiology. Microinjection of the selective OXTR agonist Thr4,Gly7-oxytocin (TGOT) significantly impairs long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway in juvenile males, but we find no effect in females. Whole-cell patch-clamp recordings show that TGOT increases spontaneous inhibitory postsynaptic currents (sIPSCs) in both sexes, while reducing spontaneous excitatory postsynaptic currents (sEPSCs) only in males. TGOT also reduces intrinsic excitability in juvenile males, whereas female excitability is unchanged. These findings reveal sex-specific effects of oxytocin on hippocampal synaptic plasticity and neuronal excitability during juvenile development. They highlight the importance of considering both sex and age as critical biological variables in studies of hippocampal function and neurodevelopmental disorders.