# Regulation of synaptic plasticity and cognitive functions by store-operated Orai1 channels

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $441,910

## Abstract

Ca2+ signaling mediates many essential roles in neurons including transmitter release, synaptic
plasticity, and gene transcription. In dendritic spines, which constitute the sites where excitatory
synaptic input is received, Ca2+ elevations drive many forms of synaptic plasticity including long-term potentiation (LTP) and spine morphogenesis. The mechanism of LTP and its physiological
consequences are of intense interest in neuroscience, driven by findings showing that it likely
forms the neurochemical basis of learning and information storage in the brain and is altered by
numerous neurodegenerative diseases, brain injuries, and drugs of abuse. However, although
the physiological phenomenon of LTP is very well characterized, its underlying molecular
mechanism is less understood. One area of uncertainty is the identity of the Ca2+ entry pathways
involved in generating spine Ca2+ signals and how these pathways interface with downstream
signaling systems. In this work, we will investigate the contributions of a relatively poorly
understood Ca2+ influx pathway formed by store-operated Orai1 channels for cognitive function,
dendritic spine Ca2+ signaling, and LTP. Orai1 channels have been extensively studied in
immune cells where they stimulate processes ranging from Ca2+-dependent gene expression to
secretion of inflammatory mediators. Although growing evidence indicates that Orai1 is highly
expressed in the brain including in many regions critical for learning and memory, the properties
of these channels and their physiological roles in the brain are poorly understood. We
hypothesize that Orai1 channels are a key mechanism for generating Ca2+ signals in dendritic
spines and make significant contributions to synaptically-evoked Ca2+ rises in spines to regulate
synaptic plasticity and cognition. Using mice lacking Orai1 or its activators, STIM1 and STIM2,
we will address this hypothesis through three specific goals: 1) evaluate the contributions of
Orai1 channels for cognitive processes related to learning, memory, and sensorimotor function
in mouse models. 2) investigate the physiological contributions of Orai1 channels for LTP,
CaMKII activation, and insertion of AMPA receptors into postsynaptic densities, and 3) examine
the role of Orai1 channels for Ca2+ signaling in dendritic spines following synaptic stimulation.
Together, these studies will address the role of a novel Ca2+ entry pathway for synaptic plasticity
and cognitive function, and ultimately facilitate efforts to target Orai1 channels for developing
novel therapeutics for cognitive dysfunctions.

## Key facts

- **NIH application ID:** 10242943
- **Project number:** 5R01NS115508-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Murali Prakriya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,910
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242943

## Citation

> US National Institutes of Health, RePORTER application 10242943, Regulation of synaptic plasticity and cognitive functions by store-operated Orai1 channels (5R01NS115508-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242943. Licensed CC0.

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