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

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 CaV1.2 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 CaV1.2 can activate RhoA signaling independently of Ca2+ and provide insights into the cellular basis of Timothy syndrome and other ASDs.

• Publication year

  2012

• Venue

  Nature Neuroscience

• Publication date

  2012-12-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nn.3307PMID 23313911PMCID 3568452
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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