The basic neurochemical mechanisms underlying the various human epilepsies are as yet unknown. Our current knowledge of the human brain in situ is extremely limited. One approach which may prove to be especially valuable is in vivo neurochemistry using intracerebral microdialysis. This method has recently been established as a means of quantifying extracellular levels of neurochemicals in specific brain regions in both anesthetized and awake, freely-moving animals. This proposal aims to extend microdialysis to use in humans and provide novel data on hippocampal neurochemistry in vivo in patients with intractable temporal lobe epilepsy (TLE). The major focus of the proposed experiments will be the role of the excitatory amino acids, glutamate and aspartate, as well as the NMDA-receptor ligands, quinolinic acid and kynurenic acid. The net balance between endogenous excitatory and inhibitory compounds will be determined by also measuring GABA, taurine, adenosine, the monoamines and the neuropeptide, somatostatin. Further information regarding metabolic activity will be determined using lactography, the on-line analysis of extracellular lactate. Measurements of the cyclic nucleotide, cAMP may suggest alterations in the number and/or function of adenylate cyclase-coupled receptors and levels of extracellular Ca++ will also be determined on-line. The association between electrophysiological and neurochemical events will be determined by simultaneous EEG monitoring using depth electrodes . A profile of in vivo neurochemistry will be generated with the emergence of inhibitory/excitatory patterns specific to TLE. In addition, dynamic data obtained via either on-line or with rapid time resolution will help determine the neurochemical substrates of seizure generation, spread and arrest. Such data will be used both to develop new treatment strategies, and as a way of focusing further cellular and molecular biological approaches to epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS028227-05
Application #
2266842
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1990-09-01
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Tan, W K; Williams, C E; During, M J et al. (1996) Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res 39:791-7
During, M J; Leone, P; Davis, K E et al. (1995) Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels. J Clin Invest 95:2403-8
Kaiser, M G; During, M J (1995) Combining laser Doppler flowmetry with microdialysis: a novel approach to investigate the coupling of regional cerebral blood flow to neuronal activity. J Neurosci Methods 60:165-73
During, M J; Fried, I; Leone, P et al. (1994) Direct measurement of extracellular lactate in the human hippocampus during spontaneous seizures. J Neurochem 62:2356-61
During, M J; Naegele, J R; O'Malley, K L et al. (1994) Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science 266:1399-403
During, M J; Spencer, D D (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607-10
Perry, V L; Young, R S; Aquila, W J et al. (1993) Effect of experimental Escherichia coli meningitis on concentrations of excitatory and inhibitory amino acids in the rabbit brain: in vivo microdialysis study. Pediatr Res 34:187-91
Geller, A I; During, M J; Haycock, J W et al. (1993) Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector. Proc Natl Acad Sci U S A 90:7603-7
During, M J; Craig, J S; Hernandez, T D et al. (1992) Effect of amygdala kindling on the in vivo release of GABA and 5-HT in the dorsal raphe nucleus in freely moving rats. Brain Res 584:36-44
During, M J; Bean, A J; Roth, R H (1992) Effects of CNS stimulants on the in vivo release of the colocalized transmitters, dopamine and neurotensin, from rat prefrontal cortex. Neurosci Lett 140:129-33

Showing the most recent 10 out of 14 publications