Late onset and regional heterogeneity of synaptic deficits in cortical PV interneurons of Shank3B-/- mice

Abstract

Epilepsy and epileptiform patterns of cortical activity are highly prevalent in autism spectrum disorders (ASDs), but the neural substrates and pathophysiological mechanisms underlying the onset of cortical dysfunction in ASD remains elusive. Reduced cortical expression of Parvalbumin (PV) has been widely observed in ASD mouse models and human postmortem studies, suggesting a crucial role of PV interneurons (PVINs) in ASD pathogenesis. Shank3B-/- mice carrying a {Delta}13-16 deletion in SHANK3 exhibit cortical hyperactivity during postnatal development and reduced sensory responses in cortical GABAergic interneurons in adulthood. However, whether these phenotypes are associated with PVIN dysfunction is unknown. Using whole-cell electrophysiology and a viral-based strategy to label PVINs during postnatal development, we performed a developmental characterization of AMPAR miniature excitatory postsynaptic currents (mEPSCs) in PVINs and pyramidal (PYR) neurons of layer (L) 2/3 mPFC in Shank3B-/- mice. Surprisingly, reduced mEPSC frequency was observed in both PYR and PVIN populations, but only in adulthood. At P15, when cortical hyperactivity is already observed, both neuron types exhibited normal mEPSC amplitude and frequency, suggesting that glutamatergic connectivity deficits in these neurons emerge as compensatory mechanisms. Additionally, we found normal mEPSCs in adult PVINs of L2/3 somatosensory cortex, revealing region-specific phenotypic differences of cortical PVINs in Shank3B-/- mice. Together, these results demonstrate that loss of Shank3 alters PVIN function but suggest that PVIN glutamatergic synapses are a suboptimal therapeutic target for normalizing early cortical imbalances in SHANK3-associated disorders. More broadly, these findings underscore the complexity of interneuron dysfunction in ASDs, prompting further exploration of region and developmental stage specific phenotypes for understanding and developing effective interventions.