Timothy Syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons

L-type voltage gated calcium channels (LTCs) play an important role in neuronal development by promoting dendritic growth and arborization(1–3). A point mutation in Ca(V)1.2 causes Timothy Syndrome (TS)(4), a neurodevelopmental disorder associated with autism spectrum disorders (ASD). We report that channels with the TS mutation cause activity-dependent dendrite retraction in rodent neurons and in induced pluripotent stem cell (iPSCs)– derived neurons from individuals with TS. Dendrite retraction is independent of calcium permeation through the mutant channel, is associated with ectopic activation of RhoA and is inhibited by over-expression of the channel associated GTPase Gem. These results suggest that Ca(V)1.2 can activate RhoA signaling independently of Ca(2+) and provide novel insights into the cellular basis of TS and other ASDs.