The Role of AMPA Receptors with Q/R-Unedited GluR2 in Neurogenesis

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DESCRIPTION (provided by applicant): Neural progenitor cells (NPC) are capable of self-renewing and differentiating into new neurons, astrocytes, and oligodendrocytes during development and adulthood. Stimulation of neurogenesis would be important to the recovery from neuronal injury during many neurodegenerative disorders including HIV-1 Associated Dementia (HAD). However, the mechanisms by which neurogenesis is regulated remain poorly understood. Glutamate, the primary neurotransmitter in the mammalian central nervous system (CNS) is increased in the CNS during HAD. Excess glutamate causes excitotoxic damage to neurons, however it may also induce neurogenesis through the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, an ionotropic glutamate receptor. We have found that human NPC express calcium-permeable AMPA receptors containing Q/R-unedited GluR2 subunits; whereas, NPC differentiated to neurons and astrocytes express calcium-impermeable AMPA receptors comprised of Q/R-edited GluR2 subunits. In addition, the activation/potentiation of AMPA receptors on NPC directs the cells to differentiate to the neuronal lineage as opposed to the astrocyte lineage and increases the development of dendritic arbors. In this study we will investigate the mechanisms through which AMPA receptors mediate differentiation of NPC. We will develop an animal model with NPC with inducible expression of adenosine deaminase (ADAR2), the enzyme responsible for Q/R-editing of GluR2 subunits, to verify our hypothesis that calcium- permeable AMPA receptor activation mediates the differentiation of NPC to neurons. Furthermore, we will utilize this animal model to test the feasibility of using AMPA receptor potentiators as a means to induce neurogenesis. This research seeks to identify a mechanism through which glutamate induces neurogenesis. Also, we will examine the possibility of using AMPA receptor stimulators as a means to induce neurogenesis. PUBLIC HEALTH RELEVANCE: The induction of neurogenesis would be important to the recovery from neuronal injury during many neurodegenerative disorders including HIV-1 Associated Dementia (HAD).