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

Jocelyn F. Krey, Sergiu P. Paşca, Aleksandr Shcheglovitov, Masayuki Yazawa, Rachel Schwemberger, Randall Rasmusson, Ricardo E. Dolmetsch

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

L-type voltage gated calcium channels have an important role in neuronal development by promoting dendritic growth and arborization. A point mutation in the gene encoding Ca V 1.2 causes Timothy syndrome, a neurodevelopmental disorder associated with autism spectrum disorders (ASDs). We report that channels with the Timothy syndrome alteration cause activity-dependent dendrite retraction in rat and mouse neurons and in induced pluripotent stem cell (iPSC)-derived neurons from individuals with Timothy syndrome. Dendrite retraction was independent of calcium permeation through the mutant channel, was associated with ectopic activation of RhoA and was inhibited by overexpression of the channel-associated GTPase Gem. These results suggest that Ca V 1.2 can activate RhoA signaling independently of Ca2+ and provide insights into the cellular basis of Timothy syndrome and other ASDs.

Original languageEnglish (US)
Pages (from-to)201-209
Number of pages9
JournalNature Neuroscience
Volume16
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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