Cognitive impairment is a serious health concern in the United States. Epidemiological studies indicate a prevalence of over 1%, and this problem can be expected to worsen with the aging of the U.S. population. In spite of the seriousness of this problem, pharmacotherapeutic treatment for this condition remain extremely limited. Basic and clinical studies have long recognized the importance of cholinergic mechanisms for the maintenance of cognitive functioning. Indeed several lines of evidence support the idea that an AChergic deficit in cerebral cortex is a causative element in cognitive impairment. Thus, an understanding of AChergic mechanisms in cortex could substantially contribute to the search for effective pharmacotherapeutic treatments for this condition. The long term goal of this project is to elucidate the cellular and molecular mechanisms by which ACh regulates neuronal excitability and function in the cerebral cortex. To that effect, we have initially focused on responses mediated through mAChRs in PFC, an association area. During the past funding cycle, we have used electrophysiological techniques in vitro rat brain slices to identify and characterize a novel cation current that appears to be one of the principal targets for AChergic regulation in this region. In the present application we propose to extend these studies: (1) by examining the role of intracellular calcium (Ca2+) in the activation of this current; (2) determining the mAChR subtypes involved; (3) identifying the signaling mechanism by which this current is activated; and (4) determining whether this current is also activated by other neurotransmitters besides ACh. These studies should extend our understanding of the cellular and molecular mechanisms by which mAChRs regulate neuronal excitability in rat PFC. This knowledge should contribute to the search for novel and effective treatments for AChergic dysfunction in general, and cognitive impairment in particular.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH049355-05A1
Application #
2616562
Study Section
Special Emphasis Panel (ZMH1-NRB-A (02))
Project Start
1993-07-01
Project End
2003-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202