Epilepsy, among the most common neurological problems, has serious psychological and social impact on those afflicted, especially on those with temporal lobe epilepsy. The intractable seizures themselves often are a major source for the dysfunction suffered by patients with epilepsy. Neuroendocrine dysfunction is one of the most common problems that affect patients with seizures. The acute changes in neuroendocrine function, like elevations in serum prolactin, so commonly accompany temporal lobe seizures that measurement of hormonal changes are used to detect the occurrence of complex partial seizures. Recent studies done on the most extensively characterized animal model for temporal lobe epilepsy, the kindled seizure model, have shown that a hypothalamic neuroendocrine system, the vasopressin magnocellular neuroendocrine system, undergoes chronic changes as a consequence of kindled seizures (Greenwood et al, 1989, 1991). The proposed research study will characterize the types of seizures which lead to enduring VP mRNA up-regulation and the time course of the up-regulation that occurs after amygdala kindling. To determine if VP mRNA up-regulation is unique or broader in scope the proposed study will characterize the effects of kindled seizures on other neuroendocrine genes. Because of the role of glutamate in epilepsy and other forms of plasticity and its' growing importance as a neurotransmitter in the hypothalamus, a particular emphasis will be placed on defining glutamate mechanisms in VP mRNA up- regulation in the magnocellular neuroendocrine system during kindling. These studies would also investigate the effect of a glutamate receptor antagonist on the VP mRNA up-regulation during kindling. The techniques of immunocytochemistry (ICC), in situ hybridization (ISH), and ICC and ISH double labeling will be used in these studies. The threshold amygdala stimulation parameters necessary to produce a significant increase in VP magnocellular neuroendocrine mRNA will be determined. The time course of the VP mRNA changes, the cellular patterns, and the stimulus necessary to produce the maximum rise in magnocellular neuroendocrine mRNA will also be delineated. In situ hybridization will also be used to measure regional hypothalamic changes in mRNA for oxytocin, somatostatin (SRIF) and corticotropin-releasing factor (CRF) during amygdala kindling. The temporal and cellular patterns of VP mRNA expression after kindling in a putative monosynaptic, excitatory amino acid pathway from the olfactory bulb to the supraoptic nucleus will be studied. Further studies on glutamate will use receptor binding assays, receptor autoradiography, and in situ hybridization of glutamate receptor subunits to determine if glutamate receptors in the hypothalamus change during kindling. These studies offer an unique opportunity to uncover mechanisms for the neuroendocrine changes that could provide further understanding of the common neuroendocrine changes in human epilepsy as well as new insights into the impact of an epileptic brain focus on brain function remote to the focus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030923-03
Application #
2268898
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-09-07
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1996-08-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Greenwood, R S; Fan, Z; McHugh, R et al. (2000) Inhibition of hippocampal kindling by metabotropic glutamate receptor antisense oligonucleotides. Mol Cell Neurosci 16:233-43
Al-Ghoul, W M; Meeker, R B; Greenwood, R S (1997) Amygdala kindling alters N-methyl-D-aspartate receptor subunit messenger RNA expression in the rat supraoptic nucleus. Neuroscience 77:985-92
al-Ghoul, W M; Meeker, R B; Greenwood, R S (1995) Kindling induces a long-lasting increase in brain nitric oxide synthase activity. Neuroreport 6:457-60
Greenwood, R S; Meeker, R B; Abdou, A et al. (1994) Kindled seizures induce a long-term increase in vasopressin mRNA. Brain Res Mol Brain Res 24:20-6
Meeker, R B; Greenwood, R S; Hayward, J N (1994) Glutamate receptors in the rat hypothalamus and pituitary. Endocrinology 134:621-9