CAPS2 promotes BDNF secretion in hippocampal neurons and is critical for the development of hippocampal GABAergic interneuron networks

Calcium-dependent protein for secretion 2 (CAPS2) is a dense-core vesicle associated protein that is involved in the secretion of brain-derived neurotrophic factor (BDNF). BDNF has a pivotal role in neuronal survival and development, including the development of inhibitory neurons and their circuits. However, it is largely unknown how CAPS2 affects BDNF secretion and what its biological significance in inhibitory neurons is. Here we reveal the role of CAPS2 in the regulated secretion of BDNF and show the effect of CAPS2 on the development of hippocampal GABAergic systems. We show that CAPS2 is colocalized with BDNF, both synaptically and extrasynaptically in axons of hippocampal neurons. Overexpression of exogenous CAPS2 in hippocampal neurons of CAPS2 knockout (KO) mice enhanced depolarization-induced BDNF exocytosis events in terms of kinetics, frequency and amplitude. We also show that in the CAPS2 KO hippocampus, BDNF secretion is reduced and GABAergic systems are impaired, including a decreased number of GABAergic neurons and their synapses, a decreased number of synaptic vesicles in inhibitory synapses and a reduced frequency and amplitude of mIPSCs. Conversely, excitatory neurons in the CAPS2 KO hippocampus were largely unaffected with respect to fEPSPs, mEPSCs and synapse number and morphology. Moreover, CAPS2 KO mice exhibited several GABA system-associated deficits, including reduced late-phase long-term potentiation at CA3-CA1 synapses, decreased hippocampal theta oscillation frequency and increased anxiety-like behavior. Collectively, these results suggest that CAPS2 promotes activity-dependent BDNF secretion during the postnatal period, which is critical for the development of hippocampal GABAergic networks.