Areas of investigation include: molecular and cellular physiology of glutamatergic transmission, mechanisms of delayed neurodegeneration induced by global ischemia, neuroprotection after ischemia or other insult and gap junction mediated intercellular communication. 

Glutamatergic transmission is the primary mode of excitation in the nervous system. Modifications of synaptic efficacy underlie development and learning and also play important roles in disease processes. NMDA receptors, one class responding to glutamate, mediate forms of long term potentiation and depression, which can underlie memory. Protein kinases and phosphatases modify single channel properties and trafficking, i.e., movement out from the cell body, dendritic synthesis, insertion into the surface membrane, removal, and recycling or degradation. Delayed neuronal death in the hippocampal CA1 following global ischemia and in CA3 following kainate induced status epilepticus results from down regulation of GluR2, the AMPA receptor subunit that limits calcium permeability of these receptors. Increased Ca2+ influx in response to endogenous glutamate then triggers cell death by Ca2+ overload. GluR2 downregulation is mediated by REST(RE-1 silencing transcription factor), which is upregulated after ischemia. In ischemic preconditioning a brief period of ischemia leads to tolerance of a longer lasting and otherwise injurious ischemic episode. We are identifying changes in gene expression responsible for ischemic tolerance after preconditioning.

Electrical synapses formed by gap junctions synchronize many types of inhibitory interneurons in the mammalian brain. Gap junction channels are formed by a hemichannel from each of the coupled cells; because of their high conductance and permeability, it was thought that hemichannels were closed until docking with another hemichannel. Now it there is evidence that hemichannels not apposed to another hemichannel can open under physiological as well as pathological conditions. We are investigating the controlling mechanisms at the level of single (hemi) channels. Hemichannels mediate intercellular signaling by secreted molecules, such as ATP, and may be involved in propagation of damage (or protection) at boundaries between normal and injured tissue. Several human diseases are caused by connexin mutations, including X-linked Charcot-Marie-Tooth disease, one type of non-syndromic deafness, one type of epilepsy, two types of cataract, and oculodentodigital dysplasia (ODDD). We are analyzing how the altered biophysics of the mutations leads to the pathology.