In the hippocampus, the center for integration of cognitive functions, nicotinic receptors (nAChRs) modulate synaptic transmission mediated by the major excitatory and inhibitory transmitters - glutamate and GABA, respectively. However, hippocampal function relies also on tonically activated glutamatergic and GABAergic receptors. In fact7 some benzodiazepines that are clinically used for treatment of epileptic seizures affect more selectively tonic (steady state) than phasic (synaptic) GABAergic activity. Yet, the effects of nicotinic ligands on tonic activities in the hippocampus are unknown. In a recent study, we have demonstrated that the tryptophan metabolite kynurenic acid (KYNA), which is largely produced and released by astrocytes in the brain, modulates nicotinic cholinergic activity in the rat hippocampus. At physiologically relevant concentrations, KYNA inhibits more potently a7 nAChRs than NMDA receptors (once believed to be the major targets for KYNA in the brain) and regulates a4B2 nAChR expression. Other lines of evidence also indicate that there might be functional cross-talk between KYNA and the nicotinic cholinergic system: (i) nicotine regulates endogenous levels of KYNA in the brain and (ii) changes in KYNA levels often parallel alterations in the nicotinic cholinergic system in such neurological disorders as schizophrenia, Alzheimer's and Parkinson's diseases (AD, PD). This proposal is designed to use convergent, multidisciplinary approaches, including electrophysiological, biochemical and molecular biological assays, to address the central hypothesis that in the hippocampus the magnitude of nAChR activity modulates the degree o tonic and phasic glutamatergic or GABAergic activities and is regulated by endogenous KYNA.
The specific aims are: (i) to investigate the effects of nAChR ligands on tonic and phasic forms of excitation or inhibition in the hippocampus; (ii) to examine how interactions between KYNA and the nicotinic cholinergic system modulate the tonic or phasic forms of GABAergic and glutamatergic activities in the hippocampus, and (iii) to determine the site of action of KYNA on o7 nAChRs, analyzing the possibility that the site for KYNA and for the allosteric potentiating ligand galantamine (that has been recent/y introduced for treatment of AD patients) on the nAChRs is one and the same. Knockout mice with null mutations in the gene that encodes the a7 nAChR subunit or the enzyme critical for ICYNA synthesis in the brain, kynurenine aminotransferase 11 (KATII), recombinant a7 nAChRs (mutants and chimeras) and different preparations (acute slices and heterologous systems) will be used to address these fundamental issues. The results of these studies win be far reaching; they will lead to a more comprehensive understanding of the means by which neuronal activity is regulated by nicotinic ligands, and provide the mechanistic basis for future development of therapeutic strategies designed to compensate, via the kynurenine pathway, for deficits in nicotinic function in disorders such as AD, PD and schizophrenia.
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