Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsenseShank3mutation

Abstract

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

Shank3 related muscular hypotonia is accompanied by increased intracellular calcium concentrations and ion channel dysregulation in striated muscle tissue

“…Using Gene Set Enrichment Analysis (GSEA), we found that the "Sarcoplasmic reticulum calcium ion transport" gene set had a considerable enrichment of upregulated SR-related genes in the Shank3Δ11(−/−) mice. SHANK3 deficiency has been shown to result in increased intracellular calcium levels in neurons of the Shank3 R1117X+/+ mice (Ali et al, 2021). Mutations or aberrations in only one of the multiple proteins involved in intracellular calcium homeostasis can cause a variety of disorders (Missiaen et al, 2000;Lee et al, 2012;Limpitikul et al, 2016;Fill and Gillespie, 2021) and can potentially speed the onset of muscle diseases (Zheng et al, 2022).…”