Poster abstracts
Poster number 60 submitted by Ileanexis Rosado-Burgos
Glutamate induces proliferation of adult hippocampal neural stem cells through its metabolism
Ileanexis Rosado-Burgos (Neuroscience Graduate Program ), Liz D. Kirby (Department of Psychology, Chronic Brain Injury Program )
Abstract:
In most adult mammals, neurons are generated via the proliferation of neural stem cells (NSCs) in two zones in the brain: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone. These newly generated neurons integrate into the hippocampus’ circuitry, improving learning and memory, and emotional regulation. To sustain this process throughout the lifespan without exhausting themselves, NSCs must delicately balance proliferation and maintenance. Glutamate, the most abundant excitatory neurotransmitter in the brain, helps keep this balance while promoting production of new neurons by inducing self-renewing proliferation of SGZ NSCs. We previously (Rieskamp, et. al) showed that glutamate induces NSC self-renewal via glutamate transport into the cell, mediated by excitatory amino acid transporter 1 (EAAT1). This work demonstrated NSCs rely on EAAT1 cell-autonomously for their maintenance, but it was not clear how glutamate transport initiated intracellular signaling.
Glutamate transport provides two stimuli: glutamate itself as a substrate for metabolism and a depolarization due to co-transport of Na+ and H+. To investigate the role of each of these potential stimuli, we treated cultured adult hippocampal NSCs with blockers or stimulators of EAAT-mediated ion influx and glutamate metabolism. First, we compared the effects of 2 EAAT1-transportable molecules: l-aspartate vs d-aspartate. Both compounds generate current during transport, but only l-aspartate can be used readily in downstream metabolism. We found that l-aspartate increased NSC proliferation, but d-aspartate decreased NSC proliferation. Next, we treated cells with glutamate plus inhibitors of the key enzyme used in metabolism of glutamate, glutamate dehydrogenase (GDH). GDH inhibitors blocked glutamate-induced NSC proliferation completely. Combined, our findings suggest that glutamate-induced NSC proliferation relies on glutamate metabolism and not depolarization. Ongoing work is investigating signaling downstream of glutamate metabolism, in particular the role of fatty acid synthesis derived from glutamate metabolites. This work will advance understanding of maintenance of this critical cell population in the healthy adult brain.
References:
Rieskamp, J. D. et al. Excitatory Amino Acid Transporter 1 Supports Adult
Hippocampal Neural Stem Cell Self-Renewal. iScience Vol. 23. Issue 7.
(2023) https://doi.org/10.1016/j.isci.2023.107068
Keywords: Neural stem cells , Glutamate metabolism , Adult neurogenesis