title: Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network.
abstract: Calcium-dependent activator protein for secretion 2 (CAPS2) is a dense-core vesicle-associated protein that is involved in the secretion of BDNF. BDNF has a pivotal role in neuronal survival and development, including the development of inhibitory neurons and their circuits. However, how CAPS2 affects BDNF secretion and its biological significance in inhibitory neurons are largely unknown. 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-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 miniature inhibitory postsynaptic currents. Conversely, excitatory neurons in the CAPS2-KO hippocampus were largely unaffected with respect to field excitatory postsynaptic potentials, miniature excitatory postsynaptic currents, 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 that is critical for the development of hippocampal GABAergic networks.
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Nakao
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Katoh-Semba
authors.forename: Emi
authors.initials: E
authors.lastname: Kinameri
authors.forename: Asako
authors.initials: A
authors.lastname: Furuya
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirase
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism* / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D059008:Time-Lapse Imaging
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C480975:CAPS2 protein, mouse; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins