Richard J. Smeyne, Ph.D.
Department of Developmental Neurobiology
St. Jude Children's Research Hospital
Affiliated Associate Professor
Department of Anatomy and Neurobiology
Email: Richard J. Smeyne
- Ph.D. Institution: Thomas Jefferson University, Department of Anatomy, Philadelphia, PA
- Postdoctoral: Roche Institute of Molecular Biology, Department of Neurosciences, Nutley, NJ
Parkinson's disease is a debilitating neurologic disorder that is characterized by a loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and is probably caused by a multifactorial process involving an interaction of gene effects, subject age, and exposure to an environmental insult. In our lab, we used the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to recapitulate the pathology of human PD in mice. Previously, we found that the C57Bl/6J and SWR/J strains of mice differ in sensitivity to MPTP. By dissecting differences in the genome of these 2 strains of mice, we have identified a single quantitative trait loci (QTL) which theoretically contains the gene(s) that underlie sensitivity to MPTP. This QTL lies within the telomeric end of mChr. 1. We are now in the process of examining the genetic code in this region to uncover the specific genes responsible for MPTP susceptibility. Our lab is also studying which cells (neurons and/or glia) are responsible for the toxicity seen following MPTP administration. Using a novel chimeric culture method, we have found that the genotype of the glial cell plays a crucial role in determining whether an SNpc cell will die after exposure to MPTP. This finding may have implications for the development of novel therapies for the treatment of Parkinson's disease. In addition to discovering the gene(s) and cell types underlying experimental Parkinsonism, we are interested in examining novel methods of neuroprotection. We have found that exposure to an enriched environment (EE) can protect SNpc neurons from MPTP-induced cell death. Using quantitative PCR methods, we have shown that exposure to an EE increases the mRNA levels of BDNF, which has been shown to be neuroprotective in a variety of injury paradigms. In addition to our findings regarding neuroprotection, we have also shown that exposure to an EE can alter the anatomical structure of neurons in various regions of the CNS.
Another project in the lab examines the effects of prenatal exposure to drugs of abuse on developmental brain disorders, including deficits in neuronal and glial cell migration, motor performance, and environmental awareness. Exposure to these drugs in adults has been shown to cause memory defects and disorders of affect. Similar behavioral changes have been observed in animal models of drug abuse. Although the behavioral symptoms of prenatal and adult drug exposure have been described, few studies have examined the developmental mechanisms that underlie these behaviors. Drugs of abuse alter the levels of neurotransmitters in the brain, and changes in neurotransmitter levels can alter cell proliferation, cell migration, formation of neural connections, and cell survival. In the prenatal CNS, cells are generated in ventricular zones and migrate long distances to their final destinations. In the adult CNS, repopulation of neurons is severely limited; however, a few neurons are generated in the subventricular zone of the forebrain and either migrate through the rostral migratory stream to repopulate the olfactory bulb or migrate laterally to repopulate the hippocampus. We are using specific cell markers and computer-aided 3-dimensional reconstruction to trace the developmental migration of these cells. This work will allow us to determine the effects of prenatal or adult exposure to drugs of abuse on the development of the CNS. Related to cell survival, we are examining if mice prenatally exposed to cocaine have an increased sensitivity to drugs, such as MPTP or kainic acid, that effect abnormal release of neurotransmitters and induce cell death.
- Chun S, Westmoreland JJ, Bayazitov IT, Eddins D, Pani AK, Smeyne RJ, Yu J, Blundon JA, Zakharenko SS. Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science. 2014 Jun 6;344(6188):1178-82. doi: 10.1126/science.1253895. PubMed PMID: 24904170.
- Pani AK, Jiao Y, Sample KJ, Smeyne RJ. Neurochemical measurement of adenosine in discrete brain regions of five strains of inbred mice. PLoS One. 2014 Mar 18;9(3):e92422. doi: 10.1371/journal.pone.0092422. eCollection 2014. PubMed PMID: 24642754; PubMed Central PMCID: PMC3958516.
- Zigmond MJ, Smeyne RJ. Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S123-7. doi: 10.1016/S1353-8020(13)70030-0. Review. PubMed PMID: 24262162.
- Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson's disease. Free Radic Biol Med. 2013 Sep;62:13-25. doi: 10.1016/j.freeradbiomed.2013.05.001. Epub 2013 May 8. Review. PubMed PMID: 23665395; PubMed Central PMCID: PMC3736736.
- Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, Engelhardt B, Hallenbeck JM, Lonser RR, Ohlfest JR, Prat A, Scarpa M, Smeyne RJ, Drewes LR, Neuwelt EA. Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab. 2013 Jan;33(1):13-21. doi: 10.1038/jcbfm.2012.153. Epub 2012 Oct 17. Review. PubMed PMID: 23072749; PubMed Central PMCID: PMC3597357.
- Gerecke KM, Jiao Y, Pagala V, Smeyne RJ. Exercise does not protect against MPTP-induced neurotoxicity in BDNF haploinsufficient mice. PLoS One. 2012;7(8):e43250. doi: 10.1371/journal.pone.0043250. Epub 2012 Aug 17. PubMed PMID: 22912838; PubMed Central PMCID: PMC3422268.