Research articleCAPS2 deficiency affects environmental enrichment-induced adult neurogenesis and differentiation/survival of newborn neurons in the hippocampal dentate gyrus
Introduction
Environmental enrichment (EE) enables greater opportunity for learning and exercise than standard laboratory living conditions, and is associated with hippocampal adult neurogenesis and neuronal maturation [14], [20], [37]. Hippocampal adult neurogenesis and maturation contributes to spatial leaning [1], [9], social interaction [16], [19], and emotional regulation [29], [33]. Recently, hippocampal adult neurogenesis has been implicated as an important link in several psychiatric disorders including major depression, schizophrenia, cognitive dysfunction, and autism spectrum disorder (ASD) [3], [11], [15], [42].
Calcium-dependent activator protein for secretion 2 (CAPS2/CADPS2) is a member of the large dense-core vesicle associated protein family [5], [17], [34], [39]. The human CAPS2 gene is located on chromosome 7q31.32, within the autism susceptibility locus 1 [8]. Further, Caps2 knockout (KO) mice show an ASD-like behavioral phenotype [27]. CAPS2 protein is widely, but specifically, expressed in the brain including within hippocampal dentate gyrus (DG) granule cells [24]. Furthermore, CAPS2 is associated with secretion of brain-derived neurotrophic factor (BDNF) [23], [25], [26], [32], which is thought to regulate hippocampal adult neurogenesis and maturation of newborn neurons [4], [22], [30], [36]. Thus, we hypothesized that CAPS2 is associated with hippocampal adult neurogenesis and maturation of newborn neurons.
To verify this hypothesis, here we analyzed hippocampal adult neurogenesis in Caps2 KO mice. To induce adult neurogenesis, we used an EE condition, and compared the number of newborn cells and their subsequent differentiation/maturation rates between wild-type (WT) and Caps2 KO mice. Our findings confirm that CAPS2 is associated with hippocampal adult neurogenesis and maturation of newborn neurons.
Section snippets
Animals
All experimental protocols were evaluated and approved by the Regulation for Animal Research at Tokyo University of Science, and performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Generation of Caps2 KO mice was described previously [27]. Male mice were housed in home cages, at most four per cage, and maintained under 12:12 light-dark cycles with ad libitum water and food until experiments. All efforts
EE does not affect body weight, water, and food consumption in WT and Caps2 KO mice
It is reported that obesity affects hippocampal BDNF expression level and adult neurogenesis [21]. Potentially, EE condition may influence food and water consumption of animals because of the activity level of mice can be up-regulated by EE condition. Therefore, we measured body weight, water, and food consumption of WT and Caps2 KO mice in both control and EE conditions to determine whether body weight and their energy requirement are affected by either condition. The body weight of Caps2 KO
Discussion
Here, we show that compared with WT mice, Caps2 KO mice exhibit: (1) similar enhancement of hippocampal BDNF expression levels; (2) significant impairment of hippocampal adult neurogenesis; and (3) suppressed maturation of newborn neurons induced by the EE condition. These findings suggest that CAPS2 deficiency affects hippocampal adult neurogenesis, and subsequent neuronal differentiation, maturation and their survival.
CAPS2 is highly expressed in hippocampal DG granule cells [24], and
Conflicts of interest
No conflicts of interest, financial or otherwise, are declared by any of the authors.
Funding
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) and KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT; grant number, 25860169).
Author contributions
K.Y., T.F. and Y.Sh. designed the research; K.Y., R.S., S.M., and Y.Sh. performed the research; R.K.-S. supported the experiments; K.Y., R.S., S.M., R.K.-S., Y.Sa., T.S. and Y.Sh. analyzed the data; K.Y., R.K.-S., Y.Sa., T.F. and Y.Sh. wrote the paper.
References (42)
- et al.
Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation
Neuron
(2011) - et al.
CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis
Neuron
(1998) - et al.
Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus
Mol. Cell. Neurosci.
(2008) - et al.
Cloning and characterization of human CADPS and CADPS2, new members of the Ca2+-dependent activator for secretion protein family
Genomics
(2003) - et al.
Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain
Exp. Neurol.
(2000) - et al.
Age-related changes in levels of brain-derived neurotrophic factor in selected brain regions of rats, normal mice and senescence-accelerated mice: a comparison to those of nerve growth factor and neurotrophin-3
Neurosci. Res.
(1998) - et al.
UNC-31/CAPS docks and primes dense core vesicles in C. elegans neurons
Biochem. Biophys. Res. Commun.
(2010) - et al.
A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor
Neurosci. Lett.
(2010) - et al.
Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats
Exp. Neurol.
(2005) - et al.
CAPS1 and CAPS2 regulate stability and recruitment of insulin granules in mouse pancreatic beta cells
Cell Metab.
(2008)