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- Title
Shank3‐deficient thalamocortical neurons show HCN channelopathy and alterations in intrinsic electrical properties.
- Authors
Idikuda, Vinay Kumar; Kumar, Virang; Shah, Nikhil; Waite, Christopher B.; Liu, Qinglian; Zhou, Lei; Zhu, Mengye; Wang, Jianbing; Wei, Fusheng
- Abstract
Key points: Shank3 increases the HCN channel surface expression in heterologous expression systems. <italic>Shank3</italic>Δ13–16 deficiency causes significant reduction in HCN2 expression and <italic>I</italic>h current amplitude in thalamocortical (TC) neurons. <italic>Shank3</italic>Δ13–16‐ but not <italic>Shank3</italic>Δ4–9‐deficient TC neurons share changes in basic electrical properties which are comparable to those of <italic>HCN2</italic>−/− TC neurons. HCN channelopathy may critically mediate events downstream from Shank3 deficiency. Abstract: <italic>SHANK3</italic> is a scaffolding protein that is highly enriched in excitatory synapses. Mutations in the <italic>SHANK3</italic> 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 <italic>Shank3</italic>Δ13–16 knockout mice, which lack exons 13–16 in the <italic>Shank3</italic> 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 <italic>Shank3</italic>Δ13–16 mice demonstrate reduced <italic>I</italic>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 <italic>HCN2</italic>−/− TC neurons but not of the TC neurons from <italic>Shank3</italic>Δ4–9 mice, which lack exons 4–9 in the <italic>Shank3</italic> 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.
- Subjects
THALAMOCORTICAL system; SCAFFOLD proteins; KNOCKOUT mice; POSTSYNAPTIC density protein; ELECTRIC properties; CYCLIC nucleotide-gated ion channels
- Publication
Journal of Physiology, 2018, Vol 596, Issue 7, p1259
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/JP275147