Hippocampal epilepsy is characterized by synchronized hyperexcitable neurons. Many of the neurons in the hippocampus release the excitatory transmitter glutamate which contributes to the excitation. The general hypothesis that endogenous neuromodulators may influence levels of excitability in the hippocampus will be examined. Specifically, we will focus on neuropeptide Y (NPY) inhibition of excitatory neurons in the epileptic human hippocampus, and in a rat model of epilepsy. NPY is found throughout the hippocampus in both neurons and in presynaptic axons. It has been suggested as one of the brain's natural anti-seizure transmitters, and its expression and distribution appears to change with epilepsy. The presynaptic role of NPY in reducing glutamate actions will be studied with whole cell recordings in slices of the human hippocampus. Using a simplified model of hyperexcitability consisting of a single self-innervating rat hippocampal neuron, we will examine the effect of NPY and specific receptor agonists to test the hypothesis that NPY acts by a presynaptic mechanism via Y2 and Y5 receptors to reduce glutamate release in neurons showing epileptiform activity. In parallel we will directly test the hypothesis that NPY blocks glutamate release presynaptically by using the dye FM1-43 to study transmitter vesicle exocytosis in glutamatergic neurons. The hypothesis that NPY is found in GABAergic neurons will be tested with dual ultrastructural immunocytochemistry. The hypothesis that changes in neuronal activity mediated by glutamate will alter levels of expression of NPY and NPY receptor Y1-Y5 mRNA will be tested with cDNA-PCR and Northern blot analyses in parallel studies of different regions of the epileptic human and rat hippocampus and in a tissue culture model of hyperexcitable rat hippocampal neurons. NPY is potentially of great interest because its primary action in the normal hippocampus appears to be one of depressing hyperexcited neurons, without a substantial effect on normal neurotransmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037788-04
Application #
6540001
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-04-15
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2005-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$310,493
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Fu, Li-Ying; van den Pol, Anthony N (2007) GABA excitation in mouse hilar neuropeptide Y neurons. J Physiol 579:445-64
Wollmann, Guido; Tattersall, Peter; van den Pol, Anthony N (2005) Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential. J Virol 79:6005-22
Li, Ying; van den Pol, Anthony N (2005) Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons. J Neurosci 25:173-83
Fu, Li-Ying; Acuna-Goycolea, Claudio; van den Pol, Anthony N (2004) Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci 24:8741-51
van den Pol, Anthony N; Acuna-Goycolea, Claudio; Clark, K Reed et al. (2004) Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection. Neuron 42:635-52
Wu, Min; Zaborszky, Laszlo; Hajszan, Tibor et al. (2004) Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons. J Neurosci 24:3527-36
Acuna-Goycolea, Claudio; van den Pol, Anthony (2004) Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J Neurosci 24:8141-52
Wu, Min; Zhang, Zongming; Leranth, Csaba et al. (2002) Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition. J Neurosci 22:7754-65
Liu, Rong-Jian; van den Pol, Anthony N; Aghajanian, George K (2002) Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 22:9453-64
van den Pol, Anthony N; Reuter, Jon D; Santarelli, Justin G (2002) Enhanced cytomegalovirus infection of developing brain independent of the adaptive immune system. J Virol 76:8842-54

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