James E. Madl, DVM, PhD
Office: 233 Physiology Building
Research Interests -- Neurotransmitter Release in Central Nervous System Disease
A growing body of evidence suggests that altered release and reuptake of neurotransmitters can contribute to the pathogenesis of many diseases of the nervous system. Stroke, hypoglycemia, hypoxia, epilepsy, amyotrophic lateral sclerosis (ALS) and other diseases produce either increased release or decreased uptake of transmitters, resulting in the accumulation of transmitter in the extracellular fluid. Overstimulation of neuronal receptors by these excess transmitters can then lead to neuronal damage or death. Metabolic processes, including the uptake and release of transmitters, vary greatly between cell types of the CNS. Understanding the cell types involved and the mechanisms by which diseases alter release/uptake of transmitters may therefore suggest new modes of therapy for these diseases or suggest a means of disease prevention.
We are using hippocampal slices and cell cultures subjected to metabolic insults as models of various disease processes. The changes in release and redistribution of transmitters such as glutamate and aspartate in response to these insults are being measured by HPLC and immunocytochemical localization of the transmitters. Our primary focus has been on the transmitter glutamate. The Na+-dependent uptake systems for glutamate are known to be affected by plasma membrane Na+, K+ and H+ gradients and membrane potential. In different diseases, some or all of these gradients affecting uptake may be altered, leading to decreased or reversed uptake in various cell types. In Parkinson's disease or ALS, other glutamate uptake systems might deplete molecules that prevent damage induced by free radicals, thereby allowing free radicals to accumulate and damage cells. Some of the pathogenic processes we are currently investigating for their effects on glutamate release and uptake include ATP depletion, acidosis, decreased ion gradients, decreased membrane potential, increased free radical levels and hyperthermia.
Madl JE, Burgesser K. 1993. Adenosine triphosphate depletion reverses sodium-dependent neuronal uptake of glutamate in rat hippocampal slices. J Neurosci 13:4429-4444.
Madl JE, Allen DL. 1995. Hyperthermia depletes adenosine triphosphate and decreases glutamate uptake in rat hippocampal slices. Neuroscience 69:395-405.
Madl JE, Royer SM. 1999. Glutamate in synaptic terminals is reduced by lack of glucose but not hypoxia in rat hippocampal slices. Neuroscience 94:417-430.
Madl JE, Royer SM. 2000. Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices. Neuroscience 96:657-664.
MacIlnay TR, Gionfriddo JR, Dubielzig RR, Powell CC, Madl JE. 2004. Evaluation of glutamate loss from damaged retinal cells of dogs with primary glaucoma. Am J Vet Res 65:776-786.