MGLUR1Α-DEPENDENT LTP NORMALISES SEX-SPECIFIC DIFFERENCES IN TEMPOROAMMONIC PLASTICITY IN A RAT MODEL OF 16P11.2-MICRODELETION

16p11.2-microdeletion is associated with intellectual disability, autism and epilepsy, with males typically more affected than females. This sexual dimorphism is reflected in 16p11.2-microdeletion rodent models, with females displaying impaired limbic circuit function. Somatostatin interneurons (SST-INs) are crucial in limbic systems, providing feedback to local principal cells (PC). SST-IN hyperexcitability has been established in 16p11.2^+/- males, but whether such dysfunction drives circuit-level alterations or displays sex-differences remains unknown. We hypothesise that SST-IN dysfunction in 16p11.2^+/- rats leads to pathway-specific dysregulation of CA1 PC synaptic inputs distinct depending on sex. Field excitatory postsynaptic potentials were recorded from acute hippocampal slices of 3-4 week-old male and female 16p11.2^+/ and wild-type rats. Long-term plasticity (LTP) was induced at temporoammonic (TA) inputs to CA1, with and without SST-IN pre-conditioning using theta-burst stimulation in Stratum oriens/alveus, reported to induce mGluR1α-dependent plasticity of SST-INs. To test the mGluR1α dependence of SST-IN preconditioning effects, additional recordings were carried out in the presence of the selective mGluR1α antagonist LY367385. Without SST-IN pre-conditioning, TA-CA1 LTP showed a sex and genotype interaction: 16p11.2^+/- males had reduced LTP compared to wild-type, whereas 16p11.2^+/- females had increased LTP. SST-IN pre-conditioning abolished this interaction, with no LTP sex- or genotype-effects. This effect was prevented by antagonism of mGluR1α. Our results indicate that SST-IN dysfunction in 16p11.2^+/- rats contributes to sex-specific circuit-level gating of synaptic plasticity. The likely mGluR1α-dependent potentiation of SST-IN inputs gates TA-CA1 LTP and normalises the opposing sex-by-genotype effects. This supports a circuit mechanism that could contribute to sex differences in 16p11.2-microdeletion.