PT  - JOURNAL ARTICLE
AU  - Kyung Chul Shin
AU  - Gowher Ali
AU  - Houda Yasmine Ali Moussa
AU  - Vijay Gupta
AU  - Alberto de la Fuente
AU  - Hyung-Goo Kim
AU  - Lawrence W Stanton
AU  - Yongsoo Park
TI  - Deletion of <em>TRPC6</em>, an autism risk gene, induces hyperexcitability in cortical neurons derived from human pluripotent stem cells
AID  - 10.1101/2022.11.14.516407
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.14.516407
4099  - http://biorxiv.org/content/early/2022/11/14/2022.11.14.516407.short
4100  - http://biorxiv.org/content/early/2022/11/14/2022.11.14.516407.full
AB  - Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder linked to numerous rare, inherited and arising de novo genetic variants. ASD often co-occurs with attention-deficit hyperactivity disorder and epilepsy, which are associated with hyperexcitability of neurons. However, the physiological and molecular mechanisms underlying hyperexcitability in ASD remain poorly understood. Transient receptor potential canonical-6 (TRPC6) is a Ca2+-permeable cation channel that regulates store-operated calcium entry (SOCE) and is a candidate risk gene for ASD. Using human pluripotent stem cell (hPSC)-derived cortical neurons, single cell calcium imaging, and electrophysiological recording, we show that TRPC6 knockout (KO) reduces SOCE signaling and leads to hyperexcitability of neurons by increasing action potential frequency and network burst frequency. Our data provide evidence that reduction of SOCE by TRPC6 KO results in neuronal hyperexcitability, which we hypothesize is an important contributor to the cellular pathophysiology underlying hyperactivity in some ASD.Competing Interest StatementThe authors have declared no competing interest.