In the hippocampus-a major center for cognitive processing in the brain- a7* nicotinic receptors (nAChRs) modulates neuronal functions and viability. Reduced activity of these nAChRs impairs cognition in rats and mice, and has been proposed to contribute to the cognitive deficits observed in patients with schizophrenia and Alzheimer's disease (AD). In these disorders, decreased a7* nAChR activity is accompanied by increased brain levels of kynurenic acid (KYNA), an astrocyte-derived kynurenine metabolite that blocks a7* nAChRs and N-methyl-D-aspartate (NMDA) receptors J Neurosci 21:7463, 2001. Using mice with a null mutation in kynurenine aminotransferase II, an enzyme critical for brain KYNA synthesis, we obtained evidence to support the concept that normal KYNA levels maintain a tonic degree of inhibition of a7* nAChRs, but not NMDA receptors [J Neurosci 24:4635, 2004]. Recently, we also reported that the nAChR allosteric potentiating ligand galantamine, a drug used to treat mild-to-moderate AD, competitively antagonizes the effect of KYNA on a7* nAChRs [J Pharmacol Exp Ther 322:48, 2007]. The present study is designed to test the central hypothesis that elevated levels of glia-derived KYNA impair hippocampal synaptic function, disrupt hippocampal neuronal structures, and cause cognitive deficits via an inhibition of a7* nAChRs that can be prevented and/or reversed by galantamine. To address this hypothesis, we will use a complementary, multidisciplinary approach. Electrophysiological, molecular biological and biochemical studies to be performed on rat and human hippocampal slices will be complemented by in vivo biochemical and behavioral studies in rats. The experiments will rely on key pharmacological tools that cause selective fluctuations in brain KYNA levels.
In aim 1, we will identify the effects of stimulation of neosynthesis of glia-derived KYNA on the activity/ expression of a7* nAChRs and other receptors in rat and human hippocampal neurons and astrocytes.
In aim 2, we will examine the effects of acute and long-term stimulation of KYNA neosynthesis on hippocampal synaptic transmission and plasticity, neuronal structures, and cognitive functions.
In aim 3, we will determine if galantamine prevents and/or reverses the effects of elevated levels of glia-derived KYNA on hippocampal a7* nAChRs, synaptic transmission and plasticity, neuronal integrity, and cognition. These translational studies will integrate data from the molecular to the behavioral level to provide a better understanding of the contribution of KYNA to the pathophysiology of catastrophic diseases such as AD and schizophrenia, and expedite the development of better treatments to improve cognitive functions known to be impaired in these diseases.
Although dysfunctions of the nicotinic cholinergic system in the hippocampus a brain region central to cognitive processing constitute a hallmark in catastrophic disorders such as Alzheimer's disease (AD) and schizophrenia, very little is known regarding potential mechanisms that make this system go awry. We have recently discovered that kynurenic acid, a metabolite whose levels are increased in the brain of patients with AD and schizophrenia, inhibits a subtype of nicotinic cholinergic receptors - the a7* receptors. As designed, the studies proposed herein will help establish a causal relationship between increased levels of kynurenic acid and decreased nicotinic functions in the hippocampus, and expedite the development of better treatments to improve the cognitive functions known to be impaired in these diseases.
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