Shank3B deficiency disrupts GABAergic synaptic transmission in pyramidal neurons of the medial prefrontal cortex region in autism spectrum disorder

Mutations in the SHANK3B gene have been strongly implicated in the pathogenesis of autism spectrum disorder (ASD). The medial prefrontal cortex (mPFC) is integral to emotional processing and social behavior, and its atypical development is closely associated with ASD pathogenesis. However, the electrophysiological characteristics of pyramidal neurons within the mPFC and the mechanisms of their synaptic transmission remain inadequately characterized. In the present study, we conducted whole-cell patch-clamp recordings on mPFC pyramidal neurons in Shank3b knockout mice. We observed significant alterations in the membrane properties and excitability of mPFC pyramidal neurons in Shank3b knockout mice; these were accompanied by reduced inhibitory postsynaptic currents and deficiencies in γ-aminobutyric acid (GABA) release or GABAA receptor transport. Additionally, RNA sequencing analysis of PFC tissue revealed differentially expressed genes in Shank3b knockout mice compared with WT mice, with these genes enriched in synaptic function and calcium channel signaling pathways. These findings are consistent with our ultrastructural observations of a reduced postsynaptic density at excitatory synapses, which may further contribute to the impaired number and morphology of pyramidal neurons in the mPFC. Our research offers new insights into the disruption of PFC circuitry that is caused by Shank3b deficiency and establishes connections between the pathophysiological mechanisms underlying ASD and synaptic structural anomalies, ion channel dysregulation, and excitatory/inhibitory imbalances. Together, these findings highlight the importance of Shank3b-mediated regulation of GABA signaling and modulation of intrinsic excitability as prospective therapeutic targets for ASD.