Weifeng Xu, Ph. D.

Xu lab studies how experience induces long-lasting changes in synaptic transmission (synaptic plasticity) that ultimately patterns the excitatory synaptic connectivity, important for information encoding in the central nervous system. We use a combination of molecular, electrophysiological and behavioral analyses in the rodent model system to study critical players in synaptic plasticity and learning and memory. Our overarching goal is to understand the molecular mechanisms of neural plasticity essential for information processing and storage in the brain, and their dysfunction in disease such as autism, schizophrenia, bipolar disorder and mental retardation.

Signaling Scaffold for Synaptic Plasticity

In one line of our research, we discovered that different scaffold proteins influence synapses differently in aspects including dependency on neuronal activity, receptor trafficking, and the kinetics of synaptic responses. These results suggest that scaffold proteins coordinate the structural and signaling interactions among receptors, chaperone proteins, and signaling cascades, and most likely control the proper signal transduction and biophysical properties at the synapses critical for learning and memory. We are now mapping the landscape of synaptic diversity and signaling specificity controlled by scaffold proteins. Using comprehensive proteomic analysis focused on synapses, we hope to start to understand the molecular logics behind the synaptic computation. Additional studies in the lab have characterized the role of Shank family proteins, associated with Autism spectrum disorders and schizophrenia, in synaptic transmission and receptor functions. 

Regulation of Calcium Homeostasis in Learning and Memory

Calcium (Ca²⁺) is the essential secondary messenger in the brain, translating extracellular events into intracellular signaling cascades important for activity-dependent neural plasticity via Calcium-binding protein, Calmodulin (CaM)-dependent processes. Dysregulation of calcium homeostasis is thought to contribute to neuropsychiatric diseases such as schizophrenia and normal aging. We focus on a CaM-binding protein, neurogranin, because it is centrally localized in principal neurons throughout the cortex and hippocampus, at the subcellular region where Calcium-signaling is essential for synaptic plasticity, and has been associated with neurological and neuropsychiatric disorders including schizophrenia and mental retardation. We found that in hippocampus, experience-dependent translation of neurogranin gates contextual memory formation, via controlling the threshold of long-term synaptic plasticity. We are currently investigating the cellular mechanisms underlying the role of neurogranin in synaptic plasticity, and the molecular mechanisms underlying the experience-dependent translation of neurogranin. We have also studied the role of neurogranin in visual cortex, given the strong implication of its involvement in experience-dependent plasticity, and potential dysfunction in cortical plasticity in schizophrenia. We found that the level of neurogranin dictates experience-dependent stabilization of excitatory synapse in the primary visual cortex. Decreased neurogranin levels led to a profound loss of excitatory synaptic transmission upon normal visual experience, via lowered threshold for long-term depression of excitatory synaptic transmission. Using neurogranin as a molecular handle, we are currently mapping the molecular landscape that coordinates experience-dependent plasticity of cortical excitatory circuits.