Homeostatic Regulation of Neural Plasticity in Health and Disease

A hyperexcitable brain circuit is a common neurological abnormality observed in patients with various psychiatric and neurodevelopmental disorders, including schizophrenia and bipolar, mood, and autism spectrum disorders. Identifying and understanding the mechanisms that regulate neuronal excitability will likely reveal novel therapeutic targets for these diseases. My laboratory utilizes various approaches including molecular and cell biology, biochemistry, electrophysiology, and mouse genetics to understand the regulation of neuronal excitability at synaptic as well as network level. Two particular areas in which my laboratory studies include:

1) Ubiquitin proteasome system (UPS)-mediated protein degradation in neural plasticity

Our recent work identified an ubiquitin E3 ligase, Murine double minute 2 (Mdm2) plays a major role in regulating synapse elimination. Our research currently focuses on the regulation of Mdm2 and its substrate p53 upon neuronal activity stimulation. We aim to understand how Mdm2-p53 signaling contributes to homeostatic control of neuronal excitability. We also investigate whether and how Mdm2-p53 signaling is disrupted in the mouse model of fragile x syndrome (FXS), the Fmr1 KO.

2) Translational control in neural plasticity

In neurons, the messenger RNA (mRNA) can be localized to distal compartments (axons or dendrites) and translated into proteins locally. This local translation is thought to provide efficient and spatial regulations for selected genes in response to stimulations. My long-term effort has identified multiple locally translated proteins involved in various neurodevelopmental events. Because an abnormal gene translation is observed in several neurodevelopmental disorders including FXS and tuberous sclerosis complex (TSC), my research aims to understand how the dysregulated protein translation, particularly near dendrites/synapse, contributes to the deficits of homeostatic synaptic and network plasticity in neurodevelopmental disorders.

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