General Research Interest
Xu Laboratory is interested in how neurons respond to external stimuli and induce changes in their neuronal properties that eventually lead to the encoding of the information in the neural circuit. This type of activity-dependent long lasting changes is generally called neural plasticity. One form of neural plasticity, the long-lasting changes in synaptic strength, synaptic plasticity is thought to be the cellular substrate for learning and memory. Membrane excitability and intracellular environment respond to incoming neural activity and fluctuate at different temporal domains with potentially different spatial constraints. These fluctuations can influence the induction and expression of synaptic plasticity.
Weifeng is interested in how these changes are coordinated and modulated, and eventually lead to circuit modification and successful coding of the incoming information. To answer these questions, Weifeng’s lab use a multi-level analyses to combine molecular biology, biochemistry, electrophysiology and behavioral approaches to investigate the functional roles of particular gene targets in regulating neural plasticity at the cellular level and learning and memory at the behavioral level.
Project I: Signaling Scaffold for Synaptic Plasticity
Neurons communicate with each other through a specialized apparatus called synapse. Neurotransmitter receptors are resided in the postsynaptic scaffold complex. Our previous work have found that PSD-MAGUK scaffold proteins have overlapping yet distinct effects on regulating properties of synaptic transmission including synapse numbers, synaptic current kinetics and activity-dependence. These results suggest a specific, coordinated and compensatory mechanism at work to maintain the synaptic function via PSD-MAGUK scaffold proteins. We also found that manipulation of different members of the Shank family proteins show different impact on synaptic strength, suggesting differential contribution of family members in maintaining synaptic strength. We are now directing our effort to identify candidate targets in synaptic scaffolds critical for mediating synaptic plasticity.
Project II: Regulation of Calcium Homeostasis in Learning and Memory
Calcium (Ca2+) influx via membrane receptors and ion channels is essential in these processes, translating extracellular events into intracellular signaling cascades, through Ca2+-calmodulin sensitive processes. Calmodulin binds to Ca2+ and is ubiquitously expressed in neurons. There are small neuronal proteins known to interact with calmodulin, and regulate the affinity of calmodulin for Ca2+ binding. Changes in these calmodulin-binding proteins will presumably influence the downstream signaling pathways that are important for synaptic plasticity and learning and memory. One example is neurogranin whose levels change in response to behavioral, environmental, and hormonal stimulation in rodent models and under pathological conditions in humans. The neurogranin gene has been associated with neurological and neuropsychiatric disorders including schizophrenia and mental retardation. We have evidence suggesting that the activity-dependent translation of neurogranin serves as a key positive modulator of neural plasticity and learning via shifting the threshold of neural plasticity. We are currently using virus-mediated gene transfer to manipulate the levels and the activity-dependent translation of neurogranin and test the functional impact on synaptic plasticity and learning. Our study will help understand the function and regulation of neurogranin important for calcium homeostasis in health and diseases, and may provide therapeutic substrate for pharmacological interventions for schizophrenia patients.