CAPS1 is involved in hippocampal synaptic plasticity and hippocampus-associated learning

Chiaki Ishii,Natsumi Shibano,Mio Yamazaki,Yo Shinoda,Yoshitake Sano,Yugo Fukazawa,Teiichi Furuichi,Yuna Kato,Tetsushi Sadakata,Tomoki Arima,Yuki Ishii

doi:10.1038/s41598-021-88009-w

Abstract

Calcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step. However, CAPS1’s role in synaptic plasticity and brain function is elusive. Herein, we showed that synaptic plasticity and learning behavior were impaired in forebrain and/or hippocampus-specific Caps1 conditional knockout (cKO) mice by means of molecular, physiological, and behavioral analyses. Neonatal Caps1 cKO mice showed a decrease in the number of docked vesicles in the hippocampal CA3 region, with no detectable changes in the distribution of other major exocytosis-related molecules. Additionally, long-term potentiation (LTP) was partially and severely impaired in the CA1 and CA3 regions, respectively. CA1 LTP was reinforced by repeated high-frequency stimuli, whereas CA3 LTP was completely abolished. Accordingly, hippocampus-associated learning was severely impaired in adeno-associated virus (AAV) infection-mediated postnatal Caps1 cKO mice. Collectively, our findings suggest that CAPS1 is a key protein involved in the cellular mechanisms underlying hippocampal synaptic release and plasticity, which is crucial for hippocampus-associated learning.

Highlights

Calcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step
To examine whether this physiological impairment was solely due to the lack of CAPS1 or secondary effects by other molecules, we confirmed the expression levels and cellular distribution patterns of six exocytosis-related proteins
Our results indicated that the expression of these presynaptic proteins did not change between Caps[1] conditional knockout (cKO) and control mice, except for a reduction in CAPS1 expression in cKO mice (Fig. 1c)

Summary

Introduction

Calcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step. We showed that synaptic plasticity and learning behavior were impaired in forebrain and/or hippocampus-specific Caps[1] conditional knockout (cKO) mice by means of molecular, physiological, and behavioral analyses. Our findings suggest that CAPS1 is a key protein involved in the cellular mechanisms underlying hippocampal synaptic release and plasticity, which is crucial for hippocampus-associated learning. Abbreviations AAV Adeno-associated virus AFC Auditory fear-conditioning CAPS1 Calcium-dependent activator protein for secretion 1 CFC Contextual fear-conditioning cKO Conditional knock out CNS Central nervous system DCV Dense-core vesicle DG Dentate gyrus fEPSP Field excitatory postsynaptic potential HPC-cKO Hippocampus-specific conditional knockout LTM Long-term memory LTP Long-term potentiation STM Short-term potentiation SV Synaptic vesicle TBS Theta-burst stimulation. Several proteins are recruited to control the assembly of the α-helix bundle of SNARE proteins[4,5], which is important for accomplishing the subsequent fusion step in a Ca2+-dependent manner

Methods

Results

Conclusion