Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network
Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network
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DOI：
10.1073/pnas.1012220108
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Furuichi, Teiichi
中科院分区：
文献类型：
--
作者：
Shinoda, Yo;Sadakata, Tetsushi;Furuichi, Teiichi
钙依赖性分泌激活蛋白2（CAPS 2）是一种参与BDNF分泌的致密核心囊泡相关蛋白。BDNF在神经元的存活和发育中具有关键作用，包括抑制性神经元及其回路的发育。然而，CAPS 2如何影响BDNF分泌及其在抑制性神经元中的生物学意义在很大程度上是未知的。在此，我们揭示了CAPS 2在调节BDNF分泌中的作用，并显示了CAPS 2对海马GABA能系统发育的影响。我们发现CAPS 2与BDNF共定位于海马神经元轴突的突触和突触外。CAPS 2-KO小鼠海马神经元中外源性CAPS 2的过表达增强了去极化诱导的BDNF胞吐事件的动力学、频率和幅度。我们还表明，在CAPS 2-KO海马，BDNF分泌减少，GABA能系统受损，包括减少的GABA能神经元及其突触，抑制性突触中突触囊泡的数量减少，和减少的频率和幅度的微型抑制性突触后电流。相反，CAPS 2-KO海马中的兴奋性神经元在很大程度上不受场兴奋性突触后电位、微型兴奋性突触后电流以及突触数量和形态的影响。此外，CAPS 2-KO小鼠表现出几种GABA系统相关的缺陷，包括减少在CA 3-CA 1突触的晚期长时程增强，海马θ振荡频率降低，焦虑样行为增加。总的来说，这些结果表明，CAPS 2促进活性依赖性BDNF分泌在出生后期间，这是至关重要的海马GABA能网络的发展。
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.