Abnormal neuronal excitability and reduced parvalbumin expression in Shank3-deficient parvalbumin neurons of the thalamic reticular nucleus

Fast-spiking, non-adaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein – and its related high calcium-buffering capacity - under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASD). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added-buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reversed the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders. Significance Statement SHANK3 is a scaffolding protein that is highly enriched in the postsynaptic density (PSD) of synapses. Mutations and deletions of the SHANK3 gene are directly connected to Phelan-McDermid syndrome (PMS) and autism spectrum disorders (ASD). However, the links between genetic alterations and abnormalities at the cellular, network, and behavioral levels remain unclear. This study uncovered abnormal physiological changes in inhibitory neurons in the thalamus. A definitive link at the cellular level is established between the Shank3 protein deficiency and the pathological basis of related neuropsychiatric disorders.