Orai1 Channels Are Essential for Amplification of Glutamate-Evoked Ca2+ Signals in Dendritic Spines to Regulate Working and Associative Memory

Anna B Toth,Mohammad Mehdi Maneshi,Geoffrey T Swanson,Murali Prakriya,Shogo Tsujikawa,Nisha Shrestha,Toshiyuki Ishii,Megumi Yamashita,Kotaro Hori,Andrew K Shum,Jelena Radulovic,Richard J Miller

doi:10.1016/j.celrep.2020.108464

Abstract

SUMMARYStore-operated Orai1 calcium channels function as highly Ca2+-selective ion channels and are broadly expressed in many tissues including the central nervous system, but their contributions to cognitive processing are largely unknown. Here, we report that many measures of synaptic, cellular, and behavioral models of learning are markedly attenuated in mice lacking Orai1 in forebrain excitatory neurons. Results with focal glutamate uncaging in hippocampal neurons support an essential role of Orai1 channels in amplifying NMDA-receptor-induced dendritic Ca2+ transients that drive activity-dependent spine morphogenesis and long-term potentiation at Schaffer collateral-CA1 synapses. Consistent with these signaling roles, mice lacking Orai1 in pyramidal neurons (but not interneurons) exhibit striking deficits in working and associative memory tasks. These findings identify Orai1 channels as essential regulators of dendritic spine Ca2+ signaling, synaptic plasticity, and cognition.

Highlights

Ca2+ release-activated Ca2+ (CRAC) channels function as a major pathway for Ca2+ entry in many non-excitable cells where they mediate critical effector functions including gene expression, cytokine production, and cell migration (Prakriya and Lewis, 2015)
Our findings indicate that Orai1 channels play a critical role in dendritic signaling by promoting the amplification of NMDA receptors (NMDARs)-mediated Ca2+ signals in dendritic spines, which is essential for inducing activity-dependent synaptic plasticity and the formation of working and associative memories
Orai1 Mediates store-operated Ca2+ entry (SOCE) in Hippocampal Neurons We previously showed that mice with a conditional deletion of Orai1 in the brain show loss of SOCE in neural progenitor cells and astrocytes (Somasundaram et al, 2014; Toth et al, 2019)

Summary

Introduction

Ca2+ release-activated Ca2+ (CRAC) channels function as a major pathway for Ca2+ entry in many non-excitable cells where they mediate critical effector functions including gene expression, cytokine production, and cell migration (Prakriya and Lewis, 2015). In spinal nociceptive neurons and hippocampal interneurons, Orai mediates SOCE and is implicated in the regulation of chronic pain and seizure-like activity (Dou et al, 2018; Hori et al, 2020; Majewski et al, 2019). We address one aspect of this larger question: the contributions of Orai channels to synaptically evoked dendritic spine Ca2+ signals in hippocampal neurons and its implications for long-term potentiation (LTP)

Results

Discussion

Conclusion