Joseph F. Margiotta, Ph.D.
|Office: 108 Block Health Science Building|
|Fax: 419-383- 3008|
BS; 1970 Fordham University, Bronx , NY PhD; 1980 State University of New York , Stony Brook , NY
Our experiments focus on chemical synapses, the functional units of cell-to-cell communication in the nervous system. At nicotinic synapses, acetylcholine (ACh) released from presynaptic nerve terminals, activates nicotinic acetylcholine receptors (nAChRs) on adjacent postsynaptic target neurons. Such synapses underlie fast excitatory transmission in all autonomic ganglia, making them essential for maintaining visceral functions that sustain life. nAChRs and by extension nicotinic synapses are also targeted in numerous neurological illnesses inclulding Alzheimer’s and Parkinson’s disease, with an annual health cost of $187 billion. Moreover, chronic nicotine exposure from tobacco smoke perturbs nAChRs and nicotinic synapses, reinforcing nicotine addiction and underlying smoking-related illnesses that yearly kill 438,000 Americans and result in $167 billion in economic losses. Despite this relevance to health and disease, little is known about mechanisms regulating the function, plasticity and formation of nicotinic synapses. We address this issue by examining the utilization and regulation of nAChR subtypes at synapses, the roles of activity, neuropeptides and growth factors in regulating nicotinic synapse formation and function, and the molecular mechanisms underlying pre- and postsynaptic differentiation.
Our studies utilize multiple experimental approaches, including whole-cell and single-channel recording, cloning and expression of neural genes, signal pathway biochemistry, and cell imaging .
The references cited below provide an introduction to our current work, much of which is directed towards understanding how neurotrophins and neuropeptides, such as BDNF and PACAP, regulate nicotinic synaptic function. Here, we recently found that BDNF and PACAP enhance transmission at nicotinic synapses, and hypothesize they do so via high-affinity cognate receptors (TrkB and PAC 1R, respectively), each triggering effector systems that differentially regulate the function, structure and formation of nicotinic synapses.
Toaccess individual synaptic components, methods were devised to evoke and record excitatory postsynaptic currents (EPSCs) at single nicotinic synapses (Fig. 1).
Tocontrol synaptic responses, transfection methods have been developed to ectopically express variant TrkB, PAC 1R nAChR, and toxin genes in single neurons (e.g. Fig. 2).Using these new approaches we are elucidating how BDNF and PACAP exert rapid and sustained actions on nicotinic synapses, and determining how the resultant signals influence nicotinic synaptogenesis. The findings are expected to uncover mechanisms that normally regulate nicotinic synapses, and that may underlie processes causing synaptic impairment in neurological illnesses, developmental disorders, and nicotine addiction.
Burns AL, D Benson, MJ Howard, and JF Margiotta (1997) Chick ciliary ganglion neurons contain transcripts coding for AChR associated protein at synapses (rapsyn). Journal of Neuroscience 17: 5016-5026.
Pardi D and JF Margiotta (1999) PACAP activates a PLC-dependent signal pathway in chick ciliary ganglion neurons that selectively inhibits a 7-containing nicotinic receptors. Journal of Neuroscience 19: 6327-6337.
Pugh PC and JF Margiotta (2000) Nicotinic acetylcholine receptor agonists promote survival and reduce apoptosis of chick ciliary ganglion neurons. Molecular and Cellular Neuroscience 15: 113-122.
McNerney ME, D Pardi, PC Pugh, Q Nai, and JF Margiotta (2000) Expression and channel properties of -bungarotoxin-sensitive acetylcholine receptors on chick ciliary and choroid neurons. Journal of Neurophysiology 84: 1314-1329.
Chen M, PC Pugh, and JF Margiotta (2001) Nicotinic synapses formed between chick ciliary ganglion neurons in culture resemble those present on the neurons in vivo. Journal of Neurobiology 47: 265-279.
Nai Q, JM Mcintosh, and JF Margiotta. (2003) Relating neuronal nicotinic acetylcholine receptor subtypes defined by subunit composition and channel function. Molecular Pharmacology 63: 311-324.
Conroy, WG, Q Liu, Q Nai, JF Margiotta, and DK Berg. (2003) Potentiation of a 7-containing nicotinic acetylcholine receptors. Molecular Pharmacology 63: 419-428.
Zhou X, Q Nai, M Chen, JD Dittus, MJ Howard, JF Margiotta (2004) Brain derived neurotrophic factor and trkB signaling in parasympathetic neurons: relevance to regulating a 7-containing nicotinic receptors and synaptic function. Journal of Neuroscience 24: 4130-4140.
Liu HB, JF Margiotta and MJ Howard (2005) BMP4 supports noradrenergic differentiation by a PKA-dependent mechanism. Developmental Biology 286:521-36.
Pugh PC and JF Margiotta (2006) PACAP support of neuronal survival requires MAPK- and activity-generated signals. Molecular and Cellular Neurosciences 31 (3): 586-595.
Pugh PC, Zhou X, Jayakar SS, and JF Margiotta (2006) Depolarization promotes survival of ciliary ganglion neurons by BDNF-dependent and independent mechanisms. Developmental Biology 291: 182-191.
Sumner AD and JF Margiotta (2008) Pituitary adenylate cyclase activating polypeptide (PACAP) alters parasympathetic
neuron gene expression in a time-dependent fashion. J. Molecular Neuroscience 36: