Antiepileptic drugs act through a variety of mechanisms to modulate neuronal hyper-excitability. Their pharmacological effects can be mediated by direct interaction with ion channels or receptors, or by alteration in the mode or level of their expression. A key objective of the present study is delineation of acute effects of specific classes of antiepileptics and steroids on hippocampal neurons studied in tissue culture and in brain slice. Somatic conductances (Na+, Ca2+, K+ and GABA-mediated C1- conductances) will be studied using patch clamp techniques on isolated CA1, CA3, and dentate neurons in culture. Intra-dendritic recordings will be obtained in a hippocampal slice preparation to study the actions of antiepileptics on modulating sustained repetitive firing of Na+-mediated dendritic action potentials, GABA-mediated dendritic inhibition and dendritic Ca2+ spikes. We will test the hypothesis that certain antiepileptics exert action on dendritic conductances which are not clearly discernable in somatic recordings. The effects of antiepileptics on the excitability of the nonmyelinated mossy fibers and Schaffer collaterals will be examined to determine if these agents can act by limiting conduction from dentate to CA3 and CA3 to CA1. Putative receptor proteins for steroids are expressed in restricted regions of hippocampus. Do appropriate steroid ligands acutely modulate voltage-gated ion channels or neurotransmitter action in neurons isolated from these regions? High resolution time-lapse video recording and laser confocal microscopy will be used to examine patterns of intracellular Ca2+ levels of hippocampal neurons in culture. Changes in [Ca2+]i will studied following exposure to the excitatory neurotransmitter glutamate. Patterns of change in [Ca2+]i will be compared between soma and dendrite from cells in different regions, and after antiepileptic and steroid application. A key question here is to determine if anti-epileptics, or steroids can effect [Ca+]i by changing intracellular release or uptake. The present studies will focus on antiepileptic drug and steroid action of specific neurons in rat hippocampus studied in both culture and slice. The long-term objective of the proposed studies is to increase our understanding of ion channel organization and Ca2+ signalling in hippocampal neurons and to define the actions of certain anti-epileptics and steroids in modulating neuronal excitability in the hippocampus.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Yale University
New Haven
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Ransom, Christopher B; Wu, Yuanming; Richerson, George B (2010) Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons. J Neurosci 30:7672-84
Radtke, C; Spies, M; Sasaki, M et al. (2007) Demyelinating diseases and potential repair strategies. Int J Dev Neurosci 25:149-53
Wu, Yuanming; Wang, Wengang; Diez-Sampedro, Ana et al. (2007) Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 56:851-65
Tokuno, Hajime A; Bradberry, Charles W; Everill, Brian et al. (2004) Local anesthetic effects of cocaethylene and isopropylcocaine on rat peripheral nerves. Brain Res 996:159-67
Everill, B; Cummins, T R; Waxman, S G et al. (2001) Sodium currents of large (Abeta-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy. Neuroscience 106:161-9
Everill, B; Kocsis, J D (2000) Nerve growth factor maintains potassium conductance after nerve injury in adult cutaneous afferent dorsal root ganglion neurons. Neuroscience 100:417-22
Yee, J M; Agulian, S; Kocsis, J D (1998) Vigabatrin enhances promoted release of GABA in neonatal rat optic nerve. Epilepsy Res 29:195-200
Honmou, O; Kocsis, J D; Richerson, G B (1995) Gabapentin potentiates the conductance increase induced by nipecotic acid in CA1 pyramidal neurons in vitro. Epilepsy Res 20:193-202
Honmou, O; Oyelese, A A; Kocsis, J D (1995) The anticonvulsant gabapentin enhances promoted release of GABA in hippocampus: a field potential analysis. Brain Res 692:273-7
Utzschneider, D A; Rand, M N; Waxman, S G et al. (1994) Nuclear and cytoplasmic Ca2+ signals in developing rat dorsal root ganglion neurons studied in excised tissue. Brain Res 635:231-7

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