This is a continuation application which has undergone two revisions. It has changed study sections at the request of Dr. Albuquerque. The objective of this project is to identify the physiological functions of the various subtypes of neuronal nicotinic acetylcholine receptors (AChRs) present in the hippocampus (the brain area mainly involved in learning and memory) and the mechanisms by which allosteric ligands control their activity. The foundation for this application rests upon the results of the studies conducted since the inception of this grant, namely that (I) a7-bearing nAChRs-the predominant nAChR subtype on hippocampal neurons-are highly permeable to Ca2+, are selectively activated by choline, a by-product of acetylcholine hydrolysis, and mediate synaptic transmission in the CA1 field of hippocampal slices; (ii) both a7 and a4b2 nAChRs are present in CA1 interneurons of hippocampal slices, and activation of these receptors facilitates the action potential-dependent release of GABA; (iii) non-competitive agonists have been identified that potentiate the activity of various nAChR subtypes. Considering these findings, the following questions have been posed: (i) What are the roles of neuronal nAChRs in modulation of synaptic activity in the hippocampus as a whole? (ii) Are there changes in the expression of functional nAChRs in the hippocampus along with in vivo development? (iii) Can a specific nAChR subtype be associated with a distinct interneuron type? (iv) What are the roles of endogenous choline in the a7 nAChR-mediated synaptic transmission in the hippocampus? (v) Does the potency or efficacy of non-competitive agonists depend on the receptor subtype? (vi) Is the a7 nAChR-mediated synaptic transmission in the hippocampus controlled by endogenous non-competitive agonists? (vii) Can this nicotinic synaptic transmission be altered by compounds that are known to act as non-competitive agonists? To address these questions, state-of-the-art technology, including infrared-assisted videomicroscopy, the patch-clamp technique, and a computerized system of mircomanipulators will be applied to neurons in the CA1 and CA3 fields of hippocampal slices. The implications of these studies can be far reaching given that the new findings, in addition to providing new insights into the understanding of the involvement of neuronal nAChRs in synaptic function, particularly in the hippocampus, may lay the groundwork for the development of efficacious therapeutic approaches to address physiopathological conditions in which the nAChR function is impaired.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-5 (01))
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Nichols, Paul L
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University of Maryland Baltimore
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Alkondon, Manickavasagom; Pereira, Edna F R; Todd, Spencer W et al. (2015) Functional G-protein-coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. Biochem Pharmacol 93:506-18
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Albuquerque, Edson X et al. (2013) Contribution of CA3 and CA1 pyramidal neurons to the tonic *7 nAChR-dependent glutamatergic input to CA1 pyramidal neurons. Neurosci Lett 554:167-71
Albuquerque, Edson X; Schwarcz, Robert (2013) Kynurenic acid as an antagonist of ýý7 nicotinic acetylcholine receptors in the brain: facts and challenges. Biochem Pharmacol 85:1027-32
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F R et al. (2012) Regulation of GABAergic inputs to CA1 pyramidal neurons by nicotinic receptors and kynurenic acid. J Pharmacol Exp Ther 341:500-9
Wang, Xiao-Dan; Notarangelo, Francesca M; Wang, Ji-Zuo et al. (2012) Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice. Brain Res 1455:1-9
Notarangelo, Francesca M; Wu, Hui-Qiu; Macherone, Anthony et al. (2012) Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain. Anal Biochem 421:573-81
Pocivavsek, Ana; Wu, Hui-Qiu; Elmer, Greg I et al. (2012) Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur J Neurosci 35:1605-12
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Albuquerque, Edson X (2012) Kynurenic acid inhibits glutamatergic transmission to CA1 pyramidal neurons via ?7 nAChR-dependent and -independent mechanisms. Biochem Pharmacol 84:1078-87
Pocivavsek, Ana; Wu, Hui-Qiu; Potter, Michelle C et al. (2011) Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36:2357-67
Alkondon, Manickavasagom; Pereira, Edna F R; Albuquerque, Edson X (2011) Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: effects of kynurenic acid. Biochem Pharmacol 82:842-51

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