Nicotinic acetylcholine receptors (nAChRs) are essential to behaviors as basic as breathing and as mysterious as motivation, memory and mood. Loss of cholinoceptive sites, evident as decreased nAChRs and deterioration of central cholinergic projections are implicated in neurodegenerative and psychiatric disorders including schizophrenia, Parkinson's disease and Alzheimer's Dementia. The challenge remains to decipher how cholinoceptive synapses are initially established, modified and maintained and, thereby to identify the regulatory mechanisms that go awry in disorders of cholinergic signaling. Prior support led to the identification of a molecular signal that regulates the expression and distribution of neuronal nAChRs -- a neuregulin 1 splice-isoform, called CRD-Nrg1. Recent work demonstrates that CRD-Nrg1 is essential for the maintenance of specific peripheral cholinoceptive synapses. Proposed studies will determine the regulatory role and signaling mechanisms of CRD-Nrg1 in the evolution of central cholinoceptive synapses using mice genetically modified to illuminate cholinergic projections and to lack one or both CRD-Nrg1 alleles. We propose to test the hypothesis that alterations in nAChR-expression and targeting, due to inherited deficits in CRD-Nrg1, disrupt the function of specific limbic synapses. In view of the essential role of such limbic relays in the memory and reinforcement of motivated and goal-directed behaviors, the proposed cellular and molecular analyses would be an important first foray into understanding how Nrg1 deficits and consequent alterations in nAChR signaling could contribute to neuro-psychiatric diseases. The proposed hypothesis is inspired by (1) new findings on Nrg1 signaling and central cholinoceptive synapses (2) reports linking polymorphisms in both the alpha7-type nAChR and the Nrg1 locus with susceptibility to, and phenotypes of, schizophrenia. (3) numerous reports linking alterations of the basal forebrain cholinergic system and limbic-cortical nAChR expression with progressive deficits in memory and motivation as seen in schizophrenia and AD. We will test whether CRD-Nrg1-signaling is required to maintain cholinoceptive sites within specific limbic areas by combined electrophysiological, immunohistochemical, molecular biological and biochemical approaches. Proposed studies exploit the use of genetically modified mice as the source of brain slices with live-labeled projections and co-cultures of area-selective microslices with target neurons of distinct CRD-Nrg1 genotype.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029071-15
Application #
6927044
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Stewart, Randall R
Project Start
1991-01-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
15
Fiscal Year
2005
Total Cost
$511,447
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Zhong, Chongbo; Du, Chuang; Hancock, Melissa et al. (2008) Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. J Neurosci 28:9111-6
Chen, Ying-Jiun J; Johnson, Madeleine A; Lieberman, Michael D et al. (2008) Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci 28:6872-83

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