Autism-associated SHANK3 haploinsufficiency causes I _h channelopathy in human neurons

Abstract

Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan-McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here we used engineered conditional mutations in human neurons to show that heterozygous and homozygous SHANK3 mutations severely and specifically impair Ih-channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih-channels reproduced these phenotypes, suggesting they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih-currents. SHANK3 protein interacted with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) forming Ih-channels, indicating that SHANK3 functions to organize HCN-channels. Our data suggest SHANK3 mutations predispose to autism, at least partially, by inducing an Ih-channelopathy that may be amenable to pharmacological intervention.

The Planar Cell Polarity Transmembrane Protein Vangl2 Promotes Dendrite, Spine and Glutamatergic Synapse Formation in the Mammalian Forebrain

“…Evidence increasingly supports that neurodevelopmental and neuroplastic processes regulating spine and glutamatergic synapses contribute to the pathogenesis of psychiatric conditions including autism, schizophrenia and major affective disorders [2,3,4,40,41,42,43]. In line with this, several PCP proteins contributing to these processes have been implicated in psychiatric pathophysiology.…”

CryoEM structure of a prokaryotic cyclic nucleotide-gated ion channel

“…HCN channels are found in the cardiac sinoatrial node and throughout the nervous system, where they open in response to membrane hyperpolarization and generate a depolarizing current responsible for rhythmic firing (1). HCN channel mutations and mistrafficking have been associated with several disorders, including sinus bradycardia, epilepsy, and autism (3,4).…”

BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method

“…S5A,B; cf. Yi et al 2016). We found that, in human ESC (hESC)-induced neurons, expression of shRNA-PalGFP-IRES-GFP-hBRaf(V600E) and shRNA-PalGFP-IRES-GFP-hBRaf (K499E) increased the levels of phosphorylated p42/44 MAPK, whereas expression of shRNA-PalGFP-IRES-GFP-hBRaf(G469E) and shRNA-PalGFP-IRES-GFP-hBRaf (K482M) decreased the levels of phosphorylated p42/44 MAPK (Supplemental Fig.…”

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