Mechanisms of synaptic competition at developing neuromuscular synapses
We are studying the mechanisms underlying synaptic competition during neural development, using neuromuscular synapses as a model system. Using transgenic mice in which the dynamics of synaptic vesicle recycling and trafficking can be monitored in vivo, we are testing the hypothesis that activity modulates presynaptic vesicle recycling and trafficking, affecting synaptic structure, strength and survival.The results of these experiments will provide fundamentally new insights into mechanisms by which activity changes synaptic function and neural circuitry during normal development, and contribute to understanding of developmental disorders such as epilepsy, autism and mental retardation. Click here for more details.
Mechanisms of neuron-astrocyte signaling underlying synapse formation and function
We are studying the mechanisms by which astrocytes modulate inhibitory synapse formation and function in the developing central nervous system. Previous work and preliminary studies in hippocampal neurons in vitro suggest that astrocytes release soluble signals into the media (astrocyte conditioned media, ACM) that increase inhibitory neuron axon elongation, branching as well as synaptogenesis, by the criteria of increasing the number of GABAergic presynaptic terminals colocalized with postsynaptic GABAAR clusters (Elmariah et al., 2004; 2005; Hughes et al., 2010). These data lead to the hypothesis that secreted signals from astrocytes mediate the formationn of inhibitory synapses during neural development. The results of these experiments will extend our understanding of how inhibitory synapses are formed during neural development, and may also contribute to understanding of disorders of development such as epilepsy, autism and mental retardation. Click here for more details.
Pathophysiologic mechanisms of CNS autoimmunity
Novel forms of encephalitis were recently identified by Dr. Josep Dalmau in the Dept. of Neurology, Hospital Clinic and University of Barcelona, Spain. These diseases are associated with antibodies to the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the GluR1 / GluR2 subunits of the AMPA receptor, among several other cell surface proteins. These disorders were initially identified in young women with ovarian teratoma who presented with psychosis or memory problems that evolved to severe complications requiring prolonged intensive care support. Prompt recognition of this disorder is important because patients often improve with treatment.
With Dr. Dalmau and his lab, we are working to study the binding of patients’ antibodies to NMDA or AMPA receptor clusters at synapses formed in cultures of rodent hippocampal neurons. We are also determining how cerebrospinal fluid from affected patients affects synapse structure and function, how NMDA receptors are cleared from synapses, and whether these affects are reversible. Collaborative efforts are underway to generate and characterize animal models of this human disease.