Recent data from this lab together with emerging results from other labs suggest that glutamate plays an important and widespread role in hypothalamic and neuroendocrine regulation. Despite the importance of hypothalamic glutamate, it has received relatively little attention compared with the attention given to other neuroactive substances also found in the medial hypothalamus. The proposed experiments focus on the excitatory amino acid glutamate, its receptors, and cellular responses to glutamate in the hypothalamus, using the rat as an experimental model. We will use immunocytochemistry and in situ hybridization to study the expression of glutamate receptor genes in the hypothalamus, using cDNA coding for AMPA and kainate types of glutamate receptors, and antisera against the receptor protein in tissue culture and in ultrathin sections from the hypothalamus. The excitotoxic role of glutamate will be examined with a silver stain which demonstrates the cell body and dendritic arbors of neurons soon after injury by glutamate. Digital Ca2+ imaging will be used to examine long-lasting intracellular Ca2+ rises after stimulation with glutamate agonists, particularly relative to possible cytotoxic injury. To test the hypothesis that the presence of glutamate during development of the neuroendocrine hypothalamus influences the subtype of receptor expressed, we will use in situ hybridization and patch clamp recording. To examine glutamate involvement in local circuitry of the hypothalamus, we will combine intracellular electrophysiology, dye-filling, and ultrastructural immunocytochemistry with glutamate antisera. These experiments should provide a better understanding of glutamate involvement in hypothalamic function. They will also address some basic questions from a cellular level, and will examine some clinically relevant experiments with glutamate toxicity. The hypothalamus is involved in the regulation of endocrine and metabolic events and glutamate may play a critical role in the health and disease of these and other systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS016296-12
Application #
2262977
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1980-03-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1996-03-31
Support Year
12
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
Obrietan, K; van den Pol, A N (1996) Neuropeptide Y depresses GABA-mediated calcium transients in developing suprachiasmatic nucleus neurons: a novel form of calcium long-term depression. J Neurosci 16:3521-33
van den Pol, A N; Strecker, G J; Dudek, F E (1996) Excitatory and inhibitory amino acids and synaptic transmission in the suprachiasmatic nucleus. Prog Brain Res 111:41-56
Romano, C; van den Pol, A N; O'Malley, K L (1996) Enhanced early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. J Comp Neurol 367:403-12
Romano, C; Sesma, M A; McDonald, C T et al. (1995) Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 355:455-69
van den Pol, A N; Romano, C; Ghosh, P (1995) Metabotropic glutamate receptor mGluR5 subcellular distribution and developmental expression in hypothalamus. J Comp Neurol 362:134-50
Obrietan, K; Van den Pol, A N (1995) Calcium hyperexcitability in neurons cultured with glutamate receptor blockade. J Neurophysiol 73:1524-36
Obrietan, K; Belousov, A B; Heller, H C et al. (1995) Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons. J Neurophysiol 74:2150-62
van den Pol, A N (1995) Presynaptic metabotropic glutamate receptors in adult and developing neurons: autoexcitation in the olfactory bulb. J Comp Neurol 359:253-71
Chen, G; Trombley, P Q; van den Pol, A N (1995) GABA receptors precede glutamate receptors in hypothalamic development;differential regulation by astrocytes. J Neurophysiol 74:1473-84
van den Pol, A N; Hermans-Borgmeyer, I; Hofer, M et al. (1994) Ionotropic glutamate-receptor gene expression in hypothalamus: localization of AMPA, kainate, and NMDA receptor RNA with in situ hybridization. J Comp Neurol 343:428-44

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