# Disruptions in primary visual cortex physiology and function in a mouse model of Timothy syndrome

## TL;DR

This study explores how a genetic disorder called Timothy syndrome affects the visual system in mice, revealing abnormal responses to visual stimuli.

## Contribution

The study identifies specific physiological and functional disruptions in the primary visual cortex of a mouse model of Timothy syndrome.

## Key findings

- TS2 mutation leads to widened action potentials in pyramidal cells of the primary visual cortex.
- TS2-neo mice show altered visual stimulus responses, favoring mid-to-high spatial frequencies over low ones.
- There is an increased density of parvalbumin-positive cells in the primary visual cortex of TS2-neo mice.

## Abstract

Timothy syndrome (TS) is a rare genetic disorder caused by mutations in the CACNA1C gene, which encodes the L-type calcium channel α1 CaV1.2 subunit. While it is expressed throughout the body, the most serious symptoms are cardiac and neurological. Classical TS type 1 (TS1) and TS type 2 (TS2) mutations cause prolonged action potentials (APs) in cardiomyocytes and in induced neurons derived from pluripotent stem cells taken from TS patients, but the effects of TS mutations on neuronal function in vivo are not fully understood. TS is frequently associated with autistic traits, which in turn have been linked to altered sensory processing. Using the TS2-neo mouse model, we analyzed the effects of TS2 mutation on the visual system. We observed a widening of APs of pyramidal cells in ex vivo patch clamp recordings and an increase in the density of parvalbumin-positive cells in the primary visual cortex. Neurons from TS2-neo mice recorded extracellularly in vivo were less likely to respond to visual stimuli of low spatial frequency, but more likely to respond to visual stimuli of mid-to-high spatial frequency, compared to those from wild-type mice. These results point to a basic processing abnormality in the visual cortex of TS2-neo mice.