Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum

Tetsushi Sadakata, Wataru Kakegawa, Yo Shinoda, Mayu Hosono, Ritsuko Katoh-Semba, Yukiko Sekine, Yumi Sato, Chihiro Saruta, Yasuki Ishizaki, Michisuke Yuzaki, Masami Kojima, Teiichi Furuichi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Ca2+-dependent activator protein for secretion 2 (CAPS2) is a protein that is essential for enhanced release of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. We previously identified dex3, a rare alternative splice variant of CAPS2, which is overrepresented in patients with autism and is missing an exon 3 critical for axonal localization. We recently reported that a mouse model CAPS2 Δx3/Δex3 expressing dex3 showed autistic-like behavioral phenotypes including impaired social interaction and cognition and increased anxiety in an unfamiliar environment. Here, we verified impairment in axonal, but not somato-dendritic, localization of dex3 protein in cerebellar granule cells and demonstrated cellular and physiological phenotypes in postnatal cerebellum of CAPS2Δx3/Δx3 mice. Interestingly, both BDNF and NT-3 were markedly reduced in axons of cerebellar granule cells, resulting in a significant decrease in their release. As a result, dex3 mice showed developmental deficits in dendritic arborization of Purkinje cells, vermian lobulation and fissurization, and granule cell precursor proliferation. Paired-pulse facilitation at parallel fiber- Purkinje cell synapses was also impaired. Together, our results indicate that CAPS2 plays an important role in subcellular locality (axonal vs. somato-dendritic) of enhanced BDNF and NT-3 release, which is indispensable for proper development of postnatal cerebellum.

Original languageEnglish
Article numbere99524
JournalPLoS One
Volume9
Issue number6
DOIs
Publication statusPublished - 2014 Jun 12

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Neurotrophin 3
protein secretion
neurotrophins
postnatal development
Brain-Derived Neurotrophic Factor
cerebellum
Cerebellum
brain
calcium
granules
mice
Purkinje Cells
Proteins
cells
Phenotype
Neuronal Plasticity
phenotype
fiber cells
Interpersonal Relations
Autistic Disorder

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum. / Sadakata, Tetsushi; Kakegawa, Wataru; Shinoda, Yo; Hosono, Mayu; Katoh-Semba, Ritsuko; Sekine, Yukiko; Sato, Yumi; Saruta, Chihiro; Ishizaki, Yasuki; Yuzaki, Michisuke; Kojima, Masami; Furuichi, Teiichi.

In: PLoS One, Vol. 9, No. 6, e99524, 12.06.2014.

Research output: Contribution to journalArticle

Sadakata, Tetsushi ; Kakegawa, Wataru ; Shinoda, Yo ; Hosono, Mayu ; Katoh-Semba, Ritsuko ; Sekine, Yukiko ; Sato, Yumi ; Saruta, Chihiro ; Ishizaki, Yasuki ; Yuzaki, Michisuke ; Kojima, Masami ; Furuichi, Teiichi. / Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum. In: PLoS One. 2014 ; Vol. 9, No. 6.
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