UCSF

Proteins of the major histocompatibility complex class I (MHC I), previously known mainly for antigen presentation to cells of the immune system, have recently been shown to play a crucial role in both developmental neural refinement and adult synaptic plasticity. However, their function in non-neuronal cell populations in the brain or the impact of cellular changes regulated by MHC I molecules on behavioral outputs have yet to be investigated. In this dissertation, I identify novel, non-immune roles for two specific classical MHC I molecules (out of as many as 50 encoded in the murine genome) in the brain. I demonstrate that H2-Kb is a negative regulator of proliferation in neural stem cells (NSCs), a unique cell type amenable to regenerative biology. Using genetic mouse models as well as primary NSC cultures, I show that deletion or knockdown of H2-Kb molecules causes increased proliferation and neurogenesis in the adult hippocampus in vivo as well as in a cell-type specific environment in vitro. Transcriptome analysis of NSCs lacking H2-Kb reveals that this enhanced proliferative potential is due to an induction of several growth factor receptor signaling pathways. I found functionally that one mechanism by which H2-Kb may exert its inhibition is through a physical interaction with fibroblast growth receptor 1, putatively dampening its signaling. Though also highly expressed in the hippocampus, I show that the other classical MHC I molecule, H2-Db, does not play a major role in NSC function. I thus probed other hippocampal processes and revealed a developmental necessity H2-Db in preserving normal locomotion, anxiety-related behavior, and spatial and associative memory. Furthermore, I show that its acute ablation in the adult hippocampus can remarkably improve hippocampus-dependent memory. The hippocampus, an extraordinary brain structure in its capacity for immense plasticity throughout life, is particularly vulnerable to deleterious conditions such as disease and aging. As MHC I molecules are known to increase in the aged and injured brain, understanding their precise functions in the hippocampus may provide opportunities to seize its neuroplastic and regenerative potential for therapeutic intervention.