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Hippocampal mossy fibers (MFs) project from dentate gyrus granule cells onto the CA2–CA3 region. MF-mediated synaptic transmission plays an important role in hippocampal learning and memory. However, the molecular mechanisms underlying MF synaptic development and subsequent functional organization are not fully understood. We previously reported that calcium-dependent activator protein for secretion 2 (CADPS2, also known as CAPS2) regulates the secretion of dense-core vesicles (DCVs). Because CADPS2 is strongly expressed in MF terminals, we hypothesized that CADPS2 regulates the development and functional organization of MF synapses by controlling the secretion of DCVs and their contents. To test this, we compared the synaptic microstructures of hippocampal MF terminals in Cadps2 knockout (KO) mice and wild-type (WT) mice by electron microscopy (EM). On postnatal day 15 (P15), KO mice exhibited morphological abnormalities in MF boutons, including smaller bouton size, a larger number of DCVs and a smaller number of post-synaptic densities (PSDs), compared with WT mice. In adults (P56), MF boutons were larger in KO mice. Synaptic vesicles (SVs) were increased but with a lower density compared with the WT. Furthermore, the number of SVs was decreased near the active zone. Moreover, MF-innervated CA3 postsynapses in KO mice displayed aberrant structures at the postsynaptic density (PSD), with an increased number of PSDs (likely because of a larger number of perforated PSDs), compared with WT mice. Taken together, our findings suggest that CADPS2 plays a critical role in MF synaptic development and functional organization. [ABSTRACT FROM AUTHOR]

In the mouse cerebellum, Ca 2+ -dependent activator protein for secretion 2 (CADPS2, CAPS2) is involved in regulated secretion from dense-core vesicles (DCVs), which contain neuropeptides including brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). Capds2 knockout (KO) mice show impaired cerebellar development in addition to autistic-like behavioral phenotypes. To understand the molecular impact caused by loss of Capds2 , we analyzed gene expression profiles in the Capds2 KO cerebellum using a GeneChip microarray and the KEGG Pathway database. Significant differential expression was observed in 1211 of 22,690 (5.34%) genes represented on the chip. The expression levels of exocytosis-related genes ( Stx5a, Syt6 ), genes encoding secretory ( Fgf2, Fgf4, Edn2 ) and synaptic proteins ( Grin2b, Gabbr1 ), neurotrophin signaling-associated genes ( Sos1, Shc1, Traf6, Psen2 ), and a gene for Rett syndrome ( Mecp2 ) were significantly changed. Taken together, these results suggest that deregulated gene expression caused by loss of Capds2 may cause developmental deficits and/or pathological symptoms, resulting in autistic-like phenotypes. [ABSTRACT FROM AUTHOR]