Aspects of excitatory/inhibitory synapses in multiple brain regions are correlated with levels of brain-derived neurotrophic factor/neurotrophin-3.

Appropriate synapse formation during development is necessary for normal brain function, and synapse impairment is often associated with brain dysfunction. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are key factors in regulating synaptic development. We previously reported that BDNF/NT-3 secretion was enhanced by calcium-dependent activator protein for secretion 2 (CADPS2). Although BDNF/NT-3 and CADPS2 are co-expressed in various brain regions, the effect of Cadps2-deficiency on brain region-specific BDNF/NT-3 levels and synaptic development remains elusive. Here, we show developmental changes of BDNF/NT-3 levels and we assess disruption of excitatory/inhibitory synapses in multiple brain regions (cerebellum, hypothalamus, striatum, hippocampus, parietal cortex and prefrontal cortex) of Cadps2 knockout (KO) mice compared with wild-type (WT) mice. Compared with WT, BDNF levels in KO mice were reduced in young/adult hippocampus, but increased in young hypothalamus, while NT-3 levels were reduced in adult cerebellum and young hippocampus, but increased in adult parietal cortex. Immunofluorescence of vGluT1, an excitatory synapse marker, and vGAT, an inhibitory synapse marker, in adult KO showed that vGluT1 was higher in the cerebellum and parietal cortex but lower in the hippocampus, whereas vGAT was lower in the hippocampus and parietal cortex compared with WT. Immunolabeling for both vGluT1 and vGAT was increased in the parietal cortex but vGAT was decreased in the cerebellum in adult KO compared with WT. These data suggest that CADPS2-mediated secretion of BDNF/NT-3 may be involved in development and maturation of synapses and in the balance between inhibitory and excitatory synapses.

CAPS2 deficiency affects environmental enrichment-induced adult neurogenesis and differentiation/survival of newborn neurons in the hippocampal dentate gyrus.

Hippocampal adult neurogenesis is observed in the subgranular zone of the dentate gyrus (DG), and is associated with hippocampal memory formation and several psychiatric disorders including autism spectrum disorder (ASD). Calcium-dependent activator protein for secretion 2 (CAPS2) is a candidate gene related to ASD, and is highly expressed in the hippocampal DG region, with Caps2 knockout (KO) mice exhibiting ASD-like behavior. Accordingly, CAPS2 is potentially associated with hippocampal adult neurogenesis, the relationship between CAPS2 and adult neurogenesis has not yet been investigated. Here, we determined whether deficit of the Caps2 gene affects hippocampal adult neurogenesis and maturation of newborn neurons. To induce adult neurogenesis, we used the environmental enrichment (EE) condition. Both wild-type (WT) and Caps2 KO mice were housed in control or EE conditions for 3 or 14days. Hippocampal levels of brain-derived neurotrophic factor (BDNF) can be used as a physiological EE conditioned marker, and were increased at 14days in the EE condition in both WT and KO mice. Newborn cells during control and EE conditions were labeled by BrdU, and the labeled cells co-immunostained with the immature and mature neuron markers, calretinin (CR) and NeuN. The ratio of CR/BrdU and NeuN/BrdU double positive cells to all of BrdU positive cells were significantly increased in WT mice housed in the EE condition for 14days compared with the control condition. Whereas KO mice in the EE condition showed no significant increase of newborn neurons. These findings suggest that CAPS2 deficiency strongly impairs hippocampal adult neurogenesis and maturation of newborn neurons.