Investigation of Schizophrenia-Associated Genetic Variants in AMPA Receptor 3, GRIA3

About This Grant

Schizophrenia (SCZ) is a chronic neuropsychiatric disorder that affects 20 million people worldwide and is among the most burdensome of all health problems, with enormous implications for individual health, quality of life, and societal costs. Therefore, elucidating disease mechanism with the ultimate goal of developing improved treatment strategies is an urgent priority. Though SCZ is highly heritable, no singular genetic cause has been found and its genetic architecture is complex. A 2022 large genetic study identified rare genetic variants that confer substantial risk for SCZ. Among the 10 most significant is GRIA3, a gene on the X chromosome which encodes GluA3, the 3rd subunit of a major receptor mediating excitatory signals in the brain, the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). AMPARs bind the neurotransmitter glutamate and are key components of the cellular mechanisms enabling the encoding, storage, and integration of information throughout the lifetime of an organism. The long-term goal of this proposal is for the principal investigator (PI) to develop as an early independent investigator at the intersection of Neuroscience and Psychiatry, and to leverage training with experts in basic neuroscience to better understand the pathological mechanisms underlying psychiatric disorders such as SCZ with the ultimate aim to identify new therapeutic targets. The major objectives of this proposal are to undergo training in concepts and techniques in basic neuroscience to investigate the functional consequences of SCZ-associated GRIA3 variants in vitro and gene expression changes in Gria3-knockout mice in vivo. The central hypothesis is that SCZ-associated variants in GRIA3 result in partial or complete loss of synaptic GluA3, and alter AMPAR assembly, trafficking, and kinetics, resulting in multiple downstream effects that are phenotypically relevant to SCZ. Aim 1 is functional characterization of SCZ-associated GRIA3 variants, including missense changes as well as those predicted to abrogate protein expression, in order to evaluate effects on RNA and protein levels, AMPAR assembly, GluA3-cell surface delivery, spine-trafficking, kinetics, and binding to interacting proteins, and synapse number and structure, and morphology in neurons and heterologous cells in vitro. Aim 2 is performing single cell transcriptomics of forebrain and various brain regions in Gria3-null mice of both sexes at 1 and 3 months of age followed by validation studies. Expected outcomes of the proposed work are elucidation of the consequences of SCZ-associated GRIA3 variants on AMPAR receptor structure and function in vitro and single-cell transcriptional changes associated with GluA3 loss in mice. In addition to the described Aims, this proposal implements a structured, individualized career development plan specifically designed to support the candidate’s career objectives and facilitate a transition to independence. This plan will involve the guidance of an expert mentoring team, course work, supervised grant writing, and hands-on technical training, all within a collaborative, rigorous, successful academic environment.