Neurons possess prominent intracellular stores of Ca2+ in specialized endoplasmic reticulum. These stores release Ca2+ that acts as a second messenger. Upon depletion, stores must then refill, and recent studies have identified a molecular pathway required for Ca2+ store refilling in the process termed capacitive Ca2+ entry (CCE). The ER resident protein Stimi senses depletion of Ca2+ stores, whereupon it forms clusters within the ER membrane and its C-terminus spans the cytosol to activate membrane ion channels of the Oral family. Orai-Stim1 and CCE play a critical role in the physiology of many cell types. Here, we will examine the role of Stimi and Orai in neural physiology using newly developed conditional genetic deletion models.
Aim 1 will examine the role of Stimi and Orai in NMDA-dependent receptor function. Preliminary studies indicate Stimi is required for NMDA receptor dependent long-term depression, and suggest a role for Stimi in activation of calcineurin. Experiments will image Ca2+ dynamics in acute tissue slices using the genetic GCaMPS reporter line developed by Dr. Bergles. 2-photon microscopy will reveal how the absence of Stimi or Orai results in changes of Ca2+ in cell compartments including spines, dendrites and nuclear envelope. Mechanistic studies will link Ca2+ dynamics with changes in synaptic function and plasticity. These studies are directly relevant to the goals of NIMH since NMDA and calcineurin pathways are important targets for understanding schizophrenia.
Aim 2 will explore the role of STIMI-Orai in diseases linked to Ali amyloid. Preliminary studies indicate that deletion of Stimi or Orai results in increased AU-amyloid generation in vivo. This finding, together with previous reports that mutations of presenilini or presenilin2 linked to familial Alzheimer's disease inhibit CCE. suggest that inhibition of CCE may be central to mechanisms of increased AB generation. Studies will define the role of STIMI. Orail and Orai2 in Ali generation, and determine how presenilin inhibits STIMI-Orai coupling to mediate CCE. Since Ali acts to influence synaptic plasticity, an integrated understanding ofthe role of STIMI and Orai in Ali generation and NMDA plasticity will define novel pathways important for synaptic function and diseases of cognition.

Public Health Relevance

Our goal is to discover the role of intracellular Ca2+ signaling in synaptic plasticity and relate this to cognitive function. We have created novel mouse genetic models that selectively alter Ca2+ stores in the endoplasmic reticulum, and have identified changes in synaptic plasticity, neural function and behavior. Proposed studies will exploit emerging techniques to define the molecular and cellular bases of neuronal physiology that is dependent on intracellular Ca2+ stores and test their role in diseases of cognition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH100024-05
Application #
9249982
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$253,506
Indirect Cost
$97,021
Name
Johns Hopkins University
Department
Type
Domestic Higher Education
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Piard, Juliette; Hu, Jia-Hua; Campeau, Philippe M et al. (2018) FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis. Hum Mol Genet 27:589-600
Diering, Graham H; Huganir, Richard L (2018) The AMPA Receptor Code of Synaptic Plasticity. Neuron 100:314-329
Heo, Seok; Diering, Graham H; Na, Chan Hyun et al. (2018) Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. Proc Natl Acad Sci U S A 115:E3827-E3836
Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:
Ryu, Changhyeon; Jang, Dong Cheol; Jung, Dayoon et al. (2017) STIM1 Regulates Somatic Ca2+ Signals and Intrinsic Firing Properties of Cerebellar Purkinje Neurons. J Neurosci 37:8876-8894
Akassoglou, Katerina; Merlini, Mario; Rafalski, Victoria A et al. (2017) In Vivo Imaging of CNS Injury and Disease. J Neurosci 37:10808-10816
Li, Ang; Liang, Wenxuan; Guan, Honghua et al. (2017) Focus scanning with feedback-control for fiber-optic nonlinear endomicroscopy. Biomed Opt Express 8:2519-2527
Wang, Qiang; Chiu, Shu-Ling; Koropouli, Eleftheria et al. (2017) Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons. Neuron 96:1084-1098.e7
Roth, Richard H; Zhang, Yong; Huganir, Richard L (2017) Dynamic imaging of AMPA receptor trafficking in vitro and in vivo. Curr Opin Neurobiol 45:51-58
Diering, Graham H; Nirujogi, Raja S; Roth, Richard H et al. (2017) Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355:511-515

Showing the most recent 10 out of 27 publications