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Shank3‐deficient thalamocortical neurons show HCN channelopathy and alterations in intrinsic electrical properties
Author(s) -
Zhu Mengye,
Idikuda Vinay Kumar,
Wang Jianbing,
Wei Fusheng,
Kumar Virang,
Shah Nikhil,
Waite Christopher B.,
Liu Qinglian,
Zhou Lei
Publication year - 2018
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp275147
Subject(s) - hcn channel , channelopathy , biology , neuroscience , excitatory postsynaptic potential , hyperpolarization (physics) , neurotransmission , microbiology and biotechnology , chemistry , inhibitory postsynaptic potential , genetics , ion channel , receptor , organic chemistry , nuclear magnetic resonance spectroscopy
Key points Shank3 increases the HCN channel surface expression in heterologous expression systems. Shank3 Δ13–16 deficiency causes significant reduction in HCN2 expression and I h current amplitude in thalamocortical (TC) neurons. Shank3 Δ13–16 ‐ but not Shank3 Δ4–9 ‐deficient TC neurons share changes in basic electrical properties which are comparable to those of HCN2 −/− TC neurons. HCN channelopathy may critically mediate events downstream from Shank3 deficiency.Abstract SHANK3 is a scaffolding protein that is highly enriched in excitatory synapses. Mutations in the SHANK3 gene have been linked to neuropsychiatric disorders especially the autism spectrum disorders. SHANK3 deficiency is known to cause impairments in synaptic transmission, but its effects on basic neuronal electrical properties that are more localized to the soma and proximal dendrites remain unclear. Here we confirmed that in heterologous expression systems two different mouse Shank3 isoforms, Shank3A and Shank3C, significantly increase the surface expression of the mouse hyperpolarization‐activated, cyclic‐nucleotide‐gated (HCN) channel. In Shank3 Δ13–16 knockout mice, which lack exons 13–16 in the Shank3 gene (both Shank3A and Shank3C are removed) and display a severe behavioural phenotype, the expression of HCN2 is reduced to an undetectable level. The thalamocortical (TC) neurons from the ventrobasal (VB) complex of Shank3 Δ13–16 mice demonstrate reduced I h current amplitude and correspondingly increased input resistance, negatively shifted resting membrane potential, and abnormal spike firing in both tonic and burst modes. Impressively, these changes closely resemble those of HCN2 −/− TC neurons but not of the TC neurons from Shank3 Δ4–9 mice, which lack exons 4–9 in the Shank3 gene (Shank3C still exists) and demonstrate moderate behavioural phenotypes. Additionally, Shank3 deficiency increases the ratio of excitatory/inhibitory balance in VB neurons but has a limited impact on the electrical properties of connected thalamic reticular (RTN) neurons. These results provide new understanding about the role of HCN channelopathy in mediating detrimental effects downstream from Shank3 deficiency.