Research Assistant Professor of Neurology
Phone: (412) 383-7604
Specialized Areas of Interest
Neuron research; Parkinson’s disease.
Dr. Smith has continued to investigate how experience may alter the vulnerability of dopamine neurons in the substantia nigra to toxic insult and the mechanisms therein. Dopamine (DA) neurons in the substantia nigra degenerate in Parkinson’s disease and this loss is believed to underlie the motor deficits characteristic of this disease. Studies conducted by this group have shown that forced exercise prior to toxic insult via infusion of 6-hydroxydopamine (6-OHDA) can prevent degeneration of the nigrostriatal pathway that would normally ensue. They have shown that pretreatment with glial cell derived neurotrophic factor (GDNF) prior to toxic insult in rats does not protect against the down regulation of dopaminergic phenotypic markers at early timepoints (2 weeks), but does prevent actual cell death and loss of striatal DA content and a restoration of phenotypic markers at 4-8 weeks. Taken together, these data suggest that GDNF prevents 6-OHDA-induced DA cell death, but that several weeks are required before these cells begin to normally express many phenotypic markers. The dose-dependent and temporal effect of GDNF on phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) in mice was assessed. GDNF increased pERK1/2 by 256-330% at the three highest doses (0.045- 4.5 µg) assessed after 24 hours. Because the two highest doses of GDNF produced the same percent increase in pERK1/2, the lab investigated if both doses would be protective against 6-OHDA toxicity. Mice received GDNF (0.45 or 4.5 µg) 6 hours prior to 6-OHDA (0.5 µg) into the striatum and were sacrificed 4 weeks later. Only the 4.5 µg dose of GDNF protected TH-immunoreactive terminals in the striatum against 6-OHDA toxicity. Interestingly, only the increase in pERK1/2 in response to 0.45 µg GDNF could be blocked by the MEK inhibitor SL-327, which suggests that the increase in pERK1/2 after the 4.5 µg dose of GDNF is not sufficient for protection or that a MEK1/2 independent pathway for activating ERK1/2 plays a role in GDNF induced protection.
Over the course of the next year, Dr. Smith will continue to investigate how experience alters the vulnerability of the nigrostriatal pathway to toxic insult. She will extend her studies on exercise to include other experiences such as stress and inflammation.
Dr. Smith's publications can be reviewed through the National Library of Medicine's publication database.
• Ad Hoc Reviewer:
Journal of Neurochemistry
Journal of Neuroscience
Pharmacology, Biochemistry, and Behavior
Physiology and Behavior