The proposed research will evaluate the physiological and ultrastructural changes that take place within the cortical neuron at the synapse in response to ischemia. Hypoxic-ischemic injury is the single most important neurological problem occurring in the perinatal period. Its presence at any time in early development can lead to lifelong neurologic deficits including mental retardation, seizures, and cerebral palsy. Long term goals of this research are to improve knowledge about process of synaptic plasticity and repair, and to develop methods of intervention that will synaptic plasticity and repair, and to develop methods of intervention that will optimize repair. The proposed studies will test the hypothesis that cortical synapses can be both reversibly and irreversibly affected by ischemia, and will identify some of the features that are related to the reversibility of ischemic injury. The pyramidal cells of rodent hippocampal CA1 have been chosen for study because of their known selective vulnerability to ischemia and their ability to produce long term potentiation. Long term potentiation (LTP) is an enhanced synaptic response that results from brief bursts of high frequency afferent stimulation. This research is designed to develop an in vitro model of cortical ischemia, using the hippocampal slice preparation, that will allow for physiologic and ultrastructural effects of ischemia to be reliably produced. An in vitro preparation affords better control of the duration of ischemia and reperfusion than in the intact animal. Specifically, the proposed experiments have been designed to determine: 1) the minimum duration of ischemia necessary to transiently abolish evoked responses in the slice; 2) the maximum period of ischemia that the cells can endure and still recover any evoked response; and 3) the maximum period of ischemia that can be endured and still allow for the recovery of LTP. Recovery from ischemia will be considered complete if LTP can be elicited at preischemic levels. An ultrastructural analysis will be performed on the same material to examine how ischemia affects synaptic density and morphology. We will attempt to correlate synaptic ultrastructural changes with the degree of electrophysiologic recovery. By comparing the process of recovery in developing tissue to that in the adult, we will test the hypothesis that repair processes are more extensive in developing tissue. Subsequently, the in vitro model will be used to quantify the effects of pharmacologic and physiologic interventions in raising the threshold for irreversible damage in adult and developing hippocampal tissue in order to assess any age dependent differences in response to therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Physician Scientist Award (K11)
Project #
5K11HD000807-02
Application #
3086977
Study Section
Mental Retardation Research and Training Committee (HDMR)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Jensen, F; Tsuji, M; Offutt, M et al. (1993) Profound, reversible energy loss in the hypoxic immature rat brain. Brain Res Dev Brain Res 73:99-105
Jensen, F E; Firkusny, I R; Mower, G D (1993) Differences in c-fos immunoreactivity due to age and mode of seizure induction. Brain Res Mol Brain Res 17:185-93
Jensen, F E; Holmes, G L; Lombroso, C T et al. (1992) Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats. Epilepsia 33:971-80
Harris, K M; Jensen, F E; Tsao, B (1992) Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 12:2685-705
Jensen, F E; Applegate, C; Burchfiel, J et al. (1991) Differential effects of perinatal hypoxia and anoxia on long term seizure susceptibility in the rat. Life Sci 49:399-407