Mechanistic Insights into IP3R1 role in Synaptic Function and Disease

Proper neuronal function relies on highly localized calcium (Ca2+) signals. Dysregulation of Ca2+ homeostasis and dynamics lead to a myriad of neurological disorders, including migraines, epilepsy and neurodegeneration. While the role of plasma membrane voltage-gated calcium channels in neuron function is well understood, there is a significant gap in our understanding of how alternative Ca2+ sources influence neuronal physiology. The main intracellular source of Ca2+ is the endoplasmic reticulum (ER). The ER releases Ca2+ through specialized channels, including inositol 1,4,5-trisphosphate receptors (IP3Rs). Previous work has implicated IP3Rs in the establishment of synaptic plasticity, a process that modifies the efficacy of neuronal connections in response to experience. Moreover, mutations in IP3R type 1 (IP3R1), the most abundant IP3R isoform in neurons, are associated with spinocerebellar ataxia (SCA) and Gillespie syndrome, diseases characterized by poor muscle control and cerebellar atrophy. Thus, ER Ca2+ release through IP3R1 seems to be central for maintaining proper neuron function; however, the underlying mechanism remains poorly understood. This proposal aims to define the functional role of IP3R1 in synaptic transmission and plasticity, and elucidate how mutations in IP3R1 alter neuronal function. IP3Rs organize in clusters in the ER membrane. Studies in non-neuronal cells have demonstrated that IP3R clustering facilitates Ca2+ release, indicating that proper IP3R function requires both individual channel activity and proper subcellular organization. This premise may also be true in neurons, given my preliminary data shows that IP3R1 selectively form clusters in postsynaptic dendritic spines that scale with neuron excitability, and IP3R1 mutations that either increase or decrease channel conductance both cause SCA. Thus, in this proposal I will test the overarching hypothesis that postsynaptic clustering of IP3R1 determines the efficacy of synaptic transmission and is necessary for synapse maintenance and plasticity. I will test this hypothesis by first defining the dynamic changes of postsynaptic IP3R1 cluster organization during synaptic plasticity (Aim 1A) and determining if changes in IP3R1 organization are accompanied by changes in Ca2+ release (Aim 1B). I will then determine if proper IP3R1 localization and clustering is necessary for synaptic plasticity (Aim 1C). Furthermore, I will determine the effects of disease-associated IP3R1 mutations on synaptic function (Aim 2A) and attempt to rescue resulting synaptic dysfunction observed in IP3R1 mutants (Aim 2B). This proposal would address fundamental questions regarding the functional significance of IP3R1 organization in determining the signaling strength of postsynaptic spines, at rest and during synaptic plasticity. Moreover, this proposal would elucidate the underlying synaptic mechanisms of a debilitating neurological disease, spinocerebellar ataxia, and identify novel therapeutic approaches. Project Number: 1F31NS147648-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Eve Gautreaux | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-L (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11316432