Adult neurogenesis in the hippocampus occurs in the well-defined neurogenic niche in the subgranular zone of the dentate gyrus. Newborn neurons are continuously generated and mature over the course of weeks to integrate into the hippocampal circuit. Adult-born immature dentate gyrus cells (DGCs) have unique functional properties that give them a privileged role in circuits that define specific behaviors, and which are critical to episodic memory formation and retrieval. In particular these neurons play important roles in an animal’s ability to separate similar patterns and disambiguate overlapping memories, processes that become impaired during normal aging and in neurodegenerative and neuropsychiatric disorders. Therefore, mechanisms that regulate adult-born DGC maturation and integration are important in understanding diverse neurological disorders including Alzheimer’s disease, schizophrenia and post-traumatic stress disorders. Kainate receptors are a class of glutamate receptor whose contributions to heterogeneous synaptic processes are still not fully understood. The premise of these studies is built upon foundational studies in which we discovered that the maturation of adult-born DGCs is more rapid after ablation of kainate receptors. We found that this effect was likely through a disruption of intracellular Cl- gradient because of an effect on a neuronal Cl- transporter. We will fully describe the altered molecular, synaptic, and functional alterations after loss of kainate receptor signaling and will test whether GABA disruption is causal to the altered integration of maturating DGCs into the hippocampal circuit. We will determine how altered maturation of adult-born DGCs affects the animal’s ability to discriminate between similar patterns and temporal overlap of episodic memories and using in vivo microendoscope imaging correlate cellular activity to behavioral measurements in a pattern separation task. The goal of this project is to examine a new mechanism by which glutamate receptors affect adult-born DGC integration by modulating GABA signaling. These studies would define novel processes that regulate adultborn neurons that could underlie the known involvement of kainate receptor signaling in mechanisms of learning and memory.
|Effective start/end date||8/1/20 → 4/30/25|
- National Institute of Neurological Disorders and Stroke (1R01NS115471-01A1)