title: Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice.
abstract: Ca(2)(+)-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in social- and anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNF-mediated coordination of brain development to autism-related behaviors and patient genotype.
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan. sadakata-1024@umin.ac.jp
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.forename: Yo
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Megumi
authors.initials: M
authors.lastname: Oka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekine
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sato
authors.forename: Chihiro
authors.initials: C
authors.lastname: Saruta
authors.forename: Hideki
authors.initials: H
authors.lastname: Miwa
authors.forename: Mika
authors.initials: M
authors.lastname: Tanaka
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001007:Anxiety; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D001931:Brain Mapping / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D005089:Exocytosis; D005091:Exons; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D012307:Risk Factors; D012919:Social Behavior
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C480975:CAPS2 protein, mouse; D002135:Calcium-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins