The active zone protein CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus

• Published in: The European journal of neuroscience Vol. 44; no. 5; pp. 2272 - 2284
• Main Authors: Kobayashi, Shizuka, Hida, Yamato, Ishizaki, Hiroyoshi, Inoue, Eiji, Tanaka-Okamoto, Miki, Yamasaki, Miwako, Miyazaki, Taisuke, Fukaya, Masahiro, Kitajima, Isao, Takai, Yoshimi, Watanabe, Masahiko, Ohtsuka, Toshihisa, Manabe, Toshiya
• Format: Journal Article
• Language: English
• Published: France Blackwell Publishing Ltd 01.09.2016
• Subjects: Animals; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Endocytosis; Excitatory Postsynaptic Potentials; excitatory synapse; Exocytosis; Mice; Mice, Inbred C57BL; Miniature Postsynaptic Potentials; neurotransmitter release; presynaptic terminal; Presynaptic Terminals - metabolism; rab GTP-Binding Proteins - metabolism; synaptic vesicle dynamics; Synaptic Vesicles - metabolism; excitatory synapse; presynaptic terminal; synaptic vesicle dynamics; neurotransmitter release
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.13331

Synaptic efficacy is determined by various factors, including the quantal size, which is dependent on the amount of neurotransmitters in synaptic vesicles at the presynaptic terminal. It is essential for stable synaptic transmission that the quantal size is kept within a constant range and that synaptic efficacy during and after repetitive synaptic activation is maintained by replenishing release sites with synaptic vesicles. However, the mechanisms for these fundamental properties have still been undetermined. We found that the active zone protein CAST (cytomatrix at the active zone structural protein) played pivotal roles in both presynaptic regulation of quantal size and recycling of endocytosed synaptic vesicles. In the CA1 region of hippocampal slices of the CAST knockout mice, miniature excitatory synaptic responses were increased in size, and synaptic depression after prolonged synaptic activation was larger, which was attributable to selective impairment of synaptic vesicle trafficking via the endosome in the presynaptic terminal likely mediated by Rab6. Therefore, CAST serves as a key molecule that regulates dynamics and neurotransmitter contents of synaptic vesicles in the excitatory presynaptic terminal in the central nervous system. A hypothetical schema of synaptic vesicle dynamics in the presynaptic terminal. (Upper) Normal dynamics of synaptic vesicles in WT mice. Following the release of glutamate, newly‐generated synaptic vesicles are transported directly or indirectly via the endosome to the pool of synaptic vesicles, which may be regulated by CAST. CAST may also regulate membrane fusion of synaptic vesicles. (Lower) Impaired synaptic vesicle dynamics in CAST KO mice or by brefeldin A. The indirect pathway via the endosome is impaired in CAST KO mice or blocked by brefeldin A. The lack of CAST may also impair membrane fusion of synaptic vesicles.