Diseases of the nervous system, ranging from epilepsy, stroke, and Alzheimer's disease, which affect millions, to rare ones such as Rett's Syndrome and Rasmussen's Encephalitis, have devastating consequences for individuals of all ages and represent increasing medical and socioeconomic problems. Although symptomatic treatments are available in some diseases, mechanism-based therapies to prevent or cure these diseases are lacking. The long-term Research Interests of our laboratory are to understand the molecular and cellular mechanisms of neurological diseases, especially those relating to mental retardation and epilepsy.
Molecular and genetic mechanisms of mental retardation
Mental retardation is a cognitive disability characterized by significant limitations both in intellectual abilities and in adaptive behaviors such as conceptual, social, and practical skills. It occurs naturally in 2%-3% of the population, as results of injury, disease, or genetics. Mutations in X-linked genes are important causes of mental retardation. Several genes associated with mental retardation have been identified, such as fmr1 in Fragile X Syndrome, mecp2 and stk9 in Rett¡¯s syndrome and ube3a in Angelman Syndrome. However, the molecular pathways that lead from the genetic mutations to mental retardation are not clear. We would like to propose that ¡°mental retardation¡± genes contribute to neuronal morphogenesis and synaptic plasticity. We will use molecular biology, electrophysiological and imaging techniques in cultured neurons and knock-out mouse models to investigate how these genes affect neuronal development and functioning.
Homeostatic regulation of neuronal network properties
Activity and experience have important roles in refining neuronal structure and synaptic strength. Neural circuits are capable of adapting their properties in a homeostatic manner to prevent hyper- or hypoactivity, allowing animals to function in a dynamic environment. Impairment of homeostatic regulation may underlie the pathogenesis of some neurological disorders such as epilepsy. However, the underlying mechanism for this form of plasticity is not well understood. Most mechanistic studies of homeostatic plasticity were performed on cultures of dissociated cortical neurons by bi-directional modulation of neuronal activity, using pharmacological reagents. For example, chronic reduction of neuronal activity by the Na+ channel blocker tetrodotoxin (TTX) increases the intrinsic excitability and the amplitude of miniature excitatory postsynaptic currents (mEPSCs) onto pyramidal cells, whereas chronic elevation of neuronal activity by GABAA receptor antagonist bicuculline decreases neuronal excitability and mEPSC amplitude. Using this in vitro paradigm, we will study the molecular mechanisms underlying homeostatic regulations of synaptic transmission, intrinsic excitability, and neuronal morphology. Recently, we provided evidence that homeostatic changes in synaptic proteins are mediated primarily by activity-dependent control of BDNF expression/secretion, and that BDNF-TrkB signaling acts upstream of the ubiquitin-proteasome system to mediate homeostatic regulation of synaptic properties. We are now characterizing the ubiquitin E3 ligases which target specific synaptic proteins, and studying the molecular pathways of activity-dependent ubiquitin conjugation and turn-over of synaptic proteins.
Modeling neurological disorders in mice
The identification of causative single-gene mutations in a subset of families with inherited disorders has provided a powerful strategy for defining the molecular mechanisms of human neurological disorders. We are generating mice in which disease-related gene can be selectively expressed or knocked out in CNS neurons in a temporally controlled manner. These mice will be potentially valuable for investigating pathogenic triggers and for identifying the initiating events of pathogenesis. At the same time, we are generating transgenic mice that will allow us to express or knock out specific genes in single neurons and label the neurons with the green fluorescent protein. These mice will be extremely useful for investigating the autonomous impacts of these genes on neuronal development and functioning.