title: Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.
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 Ca(2+) and provide insights into the cellular basis of Timothy syndrome and other ASDs.
authors: Department of Neurobiology, Stanford University School of Medicine, Stanford, California, USA.
authors: Jocelyn F
authors: JF
authors: Krey
authors: Sergiu P
authors: SP
authors: Paşca
authors: Aleksandr
authors: A
authors: Shcheglovitov
authors: Masayuki
authors: M
authors: Yazawa
authors: Rachel
authors: R
authors: Schwemberger
authors: Randall
authors: R
authors: Rasmusson
authors: Ricardo E
authors: RE
authors: Dolmetsch
mesh_terms: D000818:Animals; D001321:Autistic Disorder; D001426:Bacterial Proteins / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010775:Photic Stimulation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D016622:Silver Staining; D013576:Syndactyly / Q000235:genetics / Q000473:pathology*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D002118:Calcium; D020746:Calcium Channels, L-Type; D008164:Luminescent Proteins; D018994:Myosin Light Chains; D034741:RNA, Small Interfering; D020742:rhoA GTP-Binding Protein; D000097573:Red Fluorescent Protein; C419385:L-type calcium channel alpha(1C); C521958:Mylpf protein, mouse; C054562:yellow fluorescent protein, Bacteria