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 CAPS2Δex3/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 CAPS2Δex3/Δex3 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.
Highlights
Ca2+-dependent activator protein for secretion 2 (CAPS2) is a member of the CAPS/CADPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles [1,2,3,4,5]
In the P7 cerebellum, wild-type CAPS2 protein was mostly localized in the granule cell axons extending into the molecular layer (ML) (Fig. 1A), whereas dex3 protein was not localized in the axons in the ML and instead accumulated densely in the cell soma in the internal granule cell layer (IGL) and sparsely in the external granular layer (EGL) (Fig. 1B)
This symmetric localization pattern was more drastic in the P21 cerebellum: wild-type CAPS2 protein was localized in the ML, axon of cerebellar granule cells (Fig. 1C), whereas dex3 protein was not in the ML but accumulated in the IGL, soma and/or dendrites of cerebellar granule cells (Fig. 1D)
Summary
Ca2+-dependent activator protein for secretion 2 (CAPS2) is a member of the CAPS/CADPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles [1,2,3,4,5]. Mouse CAPS2 protein is associated with secretory vesicles containing brain-derived neurotrophic factor (BDNF) and is involved in promoting the activity-dependent release of BDNF [8,9]. We demonstrated that neurons with increased expression of dex fail to properly coordinate local BDNF release from axons [14,15]. The association of CAPS2 with autism has been suggested by the presence of copy number variations in the CAPS2 gene in autistic patients [17,18,19], and by decreased transcription of CAPS2 in the brains of people with autism [20]. It was reported that CAPS2 deletion and missense mutations of maternal origin contribute to onset [21]
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