Research

INDIVIDUAL RESEARCHER

Mark W. Fleck , Ph.D.
Associate Professor
e-mail: fleckm@mail.amc.edu

Education

1994 - Ph.D. from University of Pittsburgh

Current Research

Glutamate is the predominant neurotransmitter in the mammalian central nervous system accounting for as much as 90 percent of all fast excitatory synaptic transmission. As such, glutamate synapses are broadly involved in normal CNS functions and glutamate dysfunctions are implicated epilepsy, cognitive impairments, affective disorders, traumatic brain injury, and neurodegenerative disease. Moreover, the strength of transmission at glutamate synapses is modifiable and a likely cellular mechanism underlying learning and memory, In this laboratory, fundamental questions are examined regarding both pre- and post-synaptic contributions to maintaining synaptic strength. We use a variety of experimental approaches, primarily patch-clamp electrophysiology in combination with molecular biology, neurochemistry, and immunocytochemistry, toward a more thorough understanding of synaptic physiology. Synapses are examined in cultured neurons which release glutamate and/or receive glutamatergic synaptic inputs.  Native glutamate receptors are examined which are naturally expressed in cultured neurons in addition to recombinant receptors which are expressed in cells transfected with glutamate receptor cDNAs.  One goal of this work is to better understand the subunit pharmacology of these receptors, how subunit composition helps to determine the strength and time-course of the synaptic response, and what factors influence subunit expression in neurons.  A second goal is to employ recombinant receptors as fast electrochemical detectors to measure glutatmate release from populations of synapses in brain slices or from single synapses in culture. Together, our studies seek to understand the fundamental biophysical principles that govern synaptic transmission and how pre- and postsynaptic properties might be altered in relation to developmental and use-dependent synaptic plasticities.

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References

1. Mah SJ, Cornell E, Mitchell NA, Fleck MW (2005) Glutamate receptor trafficking: ER quality control involves ligand binding and receptor function. J Neurosci, 25(9):2215-25.



2. Pace CJ, Glick SD, Maisonneuve IM, He LW, Jokiel PA, Kuehne ME, Fleck MW (2004) Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. Eur J Pharmacol, 492(2-3):159-67.



3. Kuehne ME, He L, Jokiel PA, Pace CJ, Fleck MW, Maisonneuve IM, Glick SD, Bidlack JM (2003) Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents. J Med Chem, 46(13):2716-30.



4. Fleck MW, Cornell E, Mah SJ (2003) Amino-acid residues involved in glutamate receptor 6 kainate receptor gating and desensitization. J Neurosci, 23(4):1219-27.



5. Fleck MW (2002) Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone. J Pharmacol Exp Ther, 302(2):612-8