The importance of alpha-ketoglutarate (alphaKG) uptake to glutamatergic neurotransmission has been discovered only relatively recently. When alphaKG uptake is blocked pharmacologically in cerebellar granule cells in culture, neurotransmitter glutamate release ceases rapidly and completely. The proposed research will test whether this regulatory mechanism also transpires in vivo. The alphaKG uptake system has been found. in the brain previously, in close correlation with the distribution of EAA neurotransmitter levels. The proposed research will define specific EAAergic neuronal systems which also contain the alphaKG uptake system, and determine if some EAAergic neurons do not contain this uptake system. The alphaKG uptake system is probably an important homeostatic mechanism to regulate the activity of EAAergic neurons, since alphaKG uptake is subject to negative feedback control by the putative EAA neurotransmitters L-glutamate and L-aspartate. This feedback may be a receptor-mediated feedback, in analogy to the autoadrenoceptors of catecholaminergic neurons and muscarinic autoreceptor of cholinergic neurons. However, the structure-activity relationship of agonists at this putative receptor has not yet been identified. The proposed research will define the structure-activity relationships of EAAs which act at this putative autoreceptor regulating alphaKG uptake. Attention has not yet been directed to identifying a human disease or animal model involving dysfunction of the alphaKG uptake system. Recently, however, it has been reported that the animal model of Wernicke's encephalopathy, caused by thiamine deficiency, is marked by acute alterations in alphaKG metabolism, and by permanent depletions in EAA levels in the brain region which also exhibits neuronal lesions. The proposed research will test the involvement of alphaKG uptake and EAAergic neurotransmission in the etiology of the lesion and the pathology of the cognitive deficit, which is the outstanding pathology associated with Wernicke's encephalopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049898-03
Application #
2249279
Study Section
Behavioral Neuroscience Review Committee (BNR)
Project Start
1992-09-30
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129