Glutamate transport and regulation of adult murine hippocampal neural stem cells

About This Grant

Neural stem cells are cells that divide to create new neurons and other supporting cells in the nervous system. In adult mammalian brains, neural stem cells are rare, existing in only a few, distinct subregions. One of these subregions, the hippocampus, relies on new neurons generated by neural stem cells to support memory processes. Within the hippocampus, there are many signals that can regulate whether neural stem cells survive and continue to make new neurons throughout life. One of those signals is the abundant neurotransmitter glutamate. Glutamate stimulates neural stem cell division and new neuron production, but it is unclear how. The investigators’ data point to a surprising role of a glutamate transporter as a way that glutamate is brought into neural stem cells and then used to fuel metabolism and promote neural stem cell division. This project uses mouse models to investigate the mechanism by which glutamate promotes healthy self-renewing neural stem cell division and new neuron generation. The research portion of this project will inform the public-health-relevant field of neural stem cell transplants for brain disease/injury. The project’s research activities are coupled with several outreach activities. For instance, a new, freely available textbook for Behavioral Neuroscience launched by the lead investigator is developed further to include art and videos produced by and explaining relevant research carried out by students. By being free, the textbook reduces financial barriers to neuroscience education throughout the U.S. In addition, the project includes summer research opportunities for undergraduate students and summer lab tutorials for local high school students. Neural stem cell (NSC) interactions with their niche are critical to supporting hippocampal function in adult mammals. The adult dentate gyrus, the hippocampal subregion where NSCs reside, is characterized by abundant glutamatergic signaling from resident neuronal populations. NSCs proliferate robustly in response to glutamatergic activity, providing a parsimonious mechanism whereby neurogenesis can be linked to activity demands of local circuits. Yet, attempts to define the molecular mediator of glutamate influence on NSCs have produced perplexing findings. Though glutamate receptor activation would be the canonical mechanism, manipulating these receptors directly has produced conflicting findings. The investigators’ preliminary data suggest that NSCs interact with glutamate directly via abundantly-expressed excitatory amino acid transporters (EAATs), particularly EAAT1. The project’s objective is to investigate the role of EAAT1-mediated glutamate transport in NSC self-renewal. The central hypothesis that EAAT1 cell-autonomously supports NSC self-renewing proliferation is tested by providing metabolic stimulation in adult mice. The proposed studies will establish NSC-expressed EAAT1 as a unique mechanism by which adult NSCs can respond to niche signals. As such, the project advances foundational understanding of NSC functional capabilities. Broader Impacts are achieved through the applicability of these findings to the development of stem cell-based therapies, as well as outreach activities focused on expanding an openly accessible undergraduate textbook, incorporating undergraduates in summer research, and holding lab practicals for summer high school students. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.