The objective of this proposal is to understand the dendritic mechanisms that underlie normal and seizure states of the brain. In order to attain this objective, it is first necessary to analyze the multiple factors (e.g., synaptic and non-synaptic membrane conductances) that interact to influence neuronal excitability. Because the hippocampus is involved in important forms of abnormal discharges, both generalized and focal epilepsy, the electrical responses of hippocampal neurons will be studied using intracellular volatge recordings in the slice preparation. Very little is known about dendritic electrical properties and how they are involved in epileptic seizure discharges, although the central role of dendrites in neuronal excitability is well accepted. Therefore, it is the primary aim of this proposal to systematically analyze the non-synaptic ion specific conductances of dendrites. For this purpose we will use a novel preparation involving intradendritic recordings from physically isolated dendrites in the hippocampus. This preparation will allow more precise analysis of dendritic electrical events than previous conventional recordings from the cell body. In conjunction with this study, I will use specific channel blocking agents to test the hypothesis that potassium-dependent properties of the dendrite play a crucial role in controlling neuronal discharge. I will further test the hypothesis that convulsant and clinically relevant anticonvulsant agents have their effects by acting primarily on these dendritic properties. These studies therefore are important for a complete understanding of dendritic function in neuronal excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS023077-01A1
Application #
3406142
Study Section
Neurology A Study Section (NEUA)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Masukawa, L M; Burdette, L J; McGonigle, P et al. (1999) Physiological and anatomical correlates of the human dentate gyrus: consequences or causes of epilepsy. Adv Neurol 79:781-94
Masukawa, L M; O'Connor, W M; Burdette, L J et al. (1997) Mossy fiber reorganization and its possible physiological consequences in the dentate gyrus of epileptic humans. Adv Neurol 72:53-68
Masukawa, L M; Wang, H; O'Connor, M J et al. (1996) Prolonged field potentials evoked by 1 Hz stimulation in the dentate gyrus of temporal lobe epileptic human brain slices. Brain Res 721:132-9
Burdette, L J; Hart, G J; Masukawa, L M (1996) Changes in dentate granule cell field potentials during afterdischarge initiation triggered by 5 Hz perforant path stimulation. Brain Res 722:39-49
O'Connor, W M; Masukawa, L; Freese, A et al. (1996) Hippocampal cell distributions in temporal lobe epilepsy: a comparison between patients with and without an early risk factor. Epilepsia 37:440-9
Masukawa, L M; O'Connor, W M; Lynott, J et al. (1995) Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients. Brain Res 678:65-75
Burdette, L J; Masukawa, L M (1995) Stimulus parameters affecting paired-pulse depression of dentate granule cell field potentials. II. Low-frequency stimulation. Brain Res 680:63-72
Uruno, K; O'Connor, M J; Masukawa, L M (1995) Effects of bicuculline and baclofen on paired-pulse depression in the dentate gyrus of epileptic patients. Brain Res 695:163-72
Uruno, K; O'Connor, M J; Masukawa, L M (1994) Alterations of inhibitory synaptic responses in the dentate gyrus of temporal lobe epileptic patients. Hippocampus 4:583-93
Strowbridge, B W; Masukawa, L M; Spencer, D D et al. (1992) Hyperexcitability associated with localizable lesions in epileptic patients. Brain Res 587:158-63

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