My primary research interest in the role of GABA receptors both in the normal physiology of the brain and in pathological states, particularly epilepsy. GABA is the major inhibitory neurotransmitter in the central nervous system and dysfunction in the GABA system is a major component of the pathology of epilepsy. I am currently working in the laboratories of Drs. Steven Mennerick and Charles Zorumski on two main projects.
The first project is to explore the properties of the endogenous neurosteroid pregnenolone sulfate. Neurosteroids are steroid compounds produced de-novo within the brain. Many neurosteroids act directly on GABA receptors to augment inhibition while others such as pregnenolone sulfate have the opposite effect. Current data would suggest that pregnenolone sulfate is not present in high enough concentrations to have any relevant physiological effect. However, our recent work has demonstrated that pregenolone sulfate is activation dependent, which may allow lower concentrations than previously appreciated to have significant effects on GABA receptors. My current work is aimed at further characterizing the properties of pregnenolone sulfate to better understand its potential physiological significance.
The second project involves the study of tonic GABA currents. We recently have come to appreciate that there are two separate classes of GABA receptors that regulate neuronal behavior in different ways. The first class is the well-known synaptic or “phasic” receptors underlying inhibitory synaptic transmission. The second, more recently appreciated class is the population of extra-synaptic GABA receptors that provide a “tonic” inhibitory input to neurons. The tonic current is thought to provide a mechanism to regulate neuronal excitability and also represents a promising new target for pharmacological treatment of diseases including epilepsy. We have recently demonstrated that there is a tonic GABA current present in single neuron hippocampal microisland cultures and my current work is aimed at further characterization of this tonic GABA current.
In addition, I am interested in clinical reseach aimed at improving outcomes and quality of life in patients with epilepsy. In particular, I have been exploring the utility of flumazenil (a GABA receptor ligand) PET imaging in the presurgical evaluation of patients with both temporal lobe and extratemporal epilepsy. I also participate in pharmaceutical trials designed to better delineate the optimal use of our current treatment options and to test promising new agents.