Steven Mennerick

The broad aim of my research is to understand control of excitation and inhibition by neurotransmitters in the central nervous system. This is an important goal because neurotransmitter actions can be double-edged, underlying normal neurotransmission on the one hand and neurotoxicity on the other. In one project we are exploring the cellular and synaptic homeostatic response to physiological and pathophysiological depolarization. We find presynaptic adaptive changes in synaptic function that may serve to protect neurons from seizures or ischemia. Other studies have uncovered that the major brain cholesterol metabolite is a potential novel endogenous positive modulator of NMDA receptors, a class of glutamate receptors important in learning and memory and in vulnerability to insult.  We are exploring the impact of this modulator on network function and its potential role in modulating damage threshold to excitotoxic insults.  We are also interested in how positive modulators interact with clinically important, use-dependent negative regulators of NMDA receptor function, such as ketamine.  A final emphasis is our collaborative work to understand the mechanisms by which endogenous neuroactive steroids directly modulate GABA and glutamate receptor function. This work employs novel chemical biology tools.  For all of these studies we use electrophysiological, molecular, and imaging techniques applied to simple in vitro systems of neurons in culture and to intact brain slices, as well as to heterologous expression.