Abstract
Anterior cingulate cortex (ACC) dysfunction is implicated in the cognitive and social deficits associated with autism spectrum disorder (ASD) , yet the developmental trajectory of ACC circuit maturation in ASD remains poorly understood. Here, we examined the postnatal development of glutamatergic synaptic connectivity and intrinsic excitability in layer 2/3 pyramidal neurons (PYR) and Parvalbumin-expressing interneurons (PVIN) in the ACC of mice harboring a deletion in SHANK3 (Shank3B (-/-) ) , a well-established genetic cause of autism. We found that ACC PVINs in Shank3B (-/-) mice exhibit reduced excitability and in vivo hypoactivity as early as postnatal day 15 (P15) despite receiving normal levels of glutamatergic input. This early PVIN hypoexcitability is associated with decreased feedforward inhibition from the mediodorsal thalamus and reduced hyperpolarization-activated (I (h) ) currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. In contrast, PYRs display normal excitability and synaptic input at this stage but already exhibit reduced I (h) currents, indicating an early emergence of HCN channel dysfunction in both PYR and PVIN. By adulthood, both neuron populations undergo marked phenotypic changes, characterized by reduced glutamatergic synaptic input and divergent alterations in excitability. Together, these findings reveal a distinct sequence of early PVIN dysfunction followed by cell-type specific circuit reorganization within ACC layer 2/3 of Shank3B (-/-) mice and identify HCN channelopathy and impaired PVIN-mediated inhibition as early pathogenic features of SHANK3-related neurodevelopmental disorders.