The study of Murine double minute-2 (Mdm2) in regulating neuronal activity-dependent protein translation

The plasticity of synaptic connection is crucial for establishing proper neural circuit excitability throughout development stages, and serves an essential role in maintaining excitatory/inhibitory (E/I) balance in the central nervous system. In this thesis, I discovered potential signaling pathways that contribute to neuronal excitability regulation upon various external stimuli. In Chapter II, I focused on determining the underlying molecular pathways that elevate neuronal excitability upon activating Group 1 metabotropic glutamate receptors (Gp1 mGluRs). While multiple mechanisms have been identified that contribute to elevating local synaptic translation efficiency, it remains largely unknown how Gp1 mGluR-mediated signaling regulates general protein translation. We identified a novel function of Murine double minute 2 (Mdm2), an ubiquitin E3 ligase, which is involved in the Gp1 mGluR-mediated translational control and activation leads to the elevation of neural activity. Using a fragile X syndrome (FXS) mouse model, we demonstrated this phenomenon is modulated by FMRP-dependent Mdm2 down-regulation. This study provides a possible direction for rescuing the dysregulated Gp1 mGluR signaling observed in fragile X syndrome patients. In Chapter III, my research focuses on understanding the novel functions of Mdm2 in regulating protein translation under cellular stress conditions. While studies have previously shown that seizures could induce endoplasmic reticulum (ER) stress, I determined how acute ER stress response modulates neuronal excitability and seizure severity. Mechanistically, we found that these beneficial effects are mediated by elevated protein translation, which is triggered by the activation of Mdm2-p53 signaling, during the early ER stress response. Our findings suggest that therapeutic attempts to reduce ER stress in epilepsies may result in worsening seizure activity and therefore caution against inhibition of ER stress as a neuroprotective strategy for epilepsies.U of I OnlyAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD syste