LINK BETWEEN HCN CHANNELOPATHY AND AUDITORY HYPERSENSITIVITY IN A MOUSE MODEL OF AUTISM SPECTRUM DISORDER

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an estimated prevalence of 1:100 people worldwide. ASD is characterized by impairments in social interaction, repetitive stereotyped behaviors, and sensory-perceptual issues. We study a humanized mouse model of ASD that lacks SHANK3 (Shank3-KO) and presents social interaction deficits, repetitive behaviors and auditory hypersensitivity.
This work focuses on auditory processing abnormalities in our Shank3-KO model. We found a general hyperexcitability phenotype in the primary auditory cortex (A1) of Shank3-KO mice. Acute treatment with lamotrigine (an anticonvulsant that modulates brain excitability) ameliorates the auditory hypersensitivity phenotype. A1 proteomics screening uncovered a robust upregulation of the HCN1 channel (hyperpolarization cyclic nucleotide gated channel 1), an important excitability regulator in the brain.
We combined auditory behavior tasks, molecular biology, patch-clamp electrophysiology and virus delivery approaches to explore a possible link between the levels of HCN1, and the auditory hypersensitivity phenotype observed in our Shank3-KO model. We found that HCN1 upregulation in the A1 is persistent during development at least since postnatal day 14. Functionally, HCN-dependent intrinsic properties of Shank3-KO neurons are distinct from wild-type controls, with the most striking differences found on adult pyramidal neurons from layer 5 of the A1. Finally, we found that silencing HCN1 in the A1 rescued some of the electrophysiological properties of these neurons in adulthood. This work suggests that auditory hypersensitivity is linked to A1 hyperexcitability and that HCN1 could be a potential target to help balance cortical excitability and improve auditory phenotype.