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 socialand anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNFmediated coordination of brain development to autism-related behaviors and patient genotype.-dependent activator protein for secretion 2 (CAPS2 or CADPS2) is a member of the CAPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles (1-5). We initially identified mouse Caps2 as a potent factor promoting the release of brain-derived neurotrophic factor (BDNF) during cerebellar development (6, 7). Our subsequent knockout mouse study showed that Caps2 not only plays a role in neuronal development of the cerebrum and hippocampus as well as the cerebellum, but that it is also associated with social interaction, anxiety, and maternal and circadian behaviors in mice (7,8). We also showed that the expression of an exon 3-skipped (or -spliced out) form of CAPS2 (designated CAPS2-dex3) (8), which is now known to be a rare alternative splicing variant (9, 10), is increased in a subgroup of patients with autism and is not properly localized in axons (8). Thus, neurons overexpressing dex3 may fail to coordinate local BDNF release from axons properly (8, 9), resulting in improper brain development and function. The human CAPS2 gene locus (7q31.32) is intriguingly located within the autism susceptibility locus 1 (AUTS1) (11) on chromosome 7q31-q33, one of several susceptibility loci for autism (12). Moreover, an association of CAPS2 with autism has been suggested recently, not only by the presence of copy number variations in the CAPS2 gene in autistic patients (13-15), but also by decreased transcription of CAPS2 in the brains of people with autism (16). Thus, clarifying the biological significance of dex3 expression is an important step in elucidating the association of CAPS2 with brain circuit development and behaviors related to autism.The potential molecular risk factors for autism susceptibility have been increasingly reported (17-26) but are poorly characterized in animal models. In this report, we generated a mouse model expressing dex3 and analyzed the cellular and autistic-like behavioral phenotypes of dex3 mice. Our results support the involvement of the rare dex3 form of Caps2 in defective axonal BDNF secretion, affecting proper brain circuit development and/ or functio...

The Ca2+‐dependent activator protein for secretion (CAPS) family consists of two members (CAPS1 and CAPS2) and regulates the exocytosis of catecholamine‐containing or neuropeptide‐containing dense‐core vesicles (DCVs) at secretion sites such as nerve terminals. A large fraction of CAPS1, however, is localized in the cell soma, and we have recently shown the possible involvement of somal CAPS1 in DCV trafficking in the trans‐Golgi network. CAPS1 and CAPS2 are differentially expressed in various regions of the mouse brain but exhibit similar expression patterns in other tissues, such as the spleen. Thus, in the present study we analyzed whether CAPS2 displays similar subcellular localization and functional roles in the cell soma as CAPS1. We found that somal CAPS2 is associated with the Golgi membrane, and mediates binding and recruitment of the GDP‐bound form of ARF4 and ARF5 (members of the membrane‐trafficking small GTPase family) to the Golgi membrane. CAPS2 knockdown and overexpression of CAPS2‐binding‐deficient ARF4/ARF5 both induced accumulation of the DCV resident protein chromogranin A around the Golgi apparatus. CAPS2 knockout mice have dilated trans‐Golgi structures when viewed by electron microscopy. These results for CAPS2 strongly support our idea that the CAPS family proteins exert dual roles in DCV trafficking, mediating trafficking at both the secretion site for exocytosis and at the Golgi complex for biogenesis. Structured digital abstract http://www.uniprot.org/uniprot/Q8BYR5 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915 with http://www.uniprot.org/uniprot/P84084 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0006 (http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293663) http://www.uniprot.org/uniprot/Q8BYR5 and http://www.uniprot.org/uniprot/O70480 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0403 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0416 (http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293847) http://www.uniprot.org/uniprot/Q8BYR5 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915 with http://www.uniprot.org/uniprot/P61750 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0007 (View Interaction: http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293603, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293623) http://www.uniprot.org/uniprot/Q8BYR5 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915 with http://www.uniprot.org/uniprot/P84084 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0007 (View Interaction: http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293582, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293641, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8293690) http://www.uniprot.org/uniprot/Q9JKK1 and http://www.uniprot.org/uniprot/Q8BYR5 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0403 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0416 (View Interaction:...

a b s t r a c t Ca 2+ -dependent activator protein for secretion 2 (CAPS2 or CADPS2) facilitates secretion and trafficking of dense-core vesicles. Recent genome-wide association studies of autism have identified several microdeletions due to copy number variation (CNV) in one of the chromosome 7q31.32 alleles on which the locus for CAPS2 is located in autistic patients. To evaluate the biological significance of reducing CAPS2 copy number, we analyzed CAPS2 heterozygous mice. Our present findings suggest that adequate levels of CAPS2 protein are critical for normal brain development and behavior, and that allelic changes due to CNV may contribute to autistic symptoms in combination with deficits in other autism-associated genes.