The ability of the adult nervous system to modify its response based on past experience is a fundamental concept of behavior. The mechanism for this adaptive change is unknown, but it is believed to occur at the synapse. Long term potentiation (LTP) and kindling are two models of synaptic plasticity that are characterized by a long lasting increase in synaptic transmission. LTP describes a persistent enhancement in synaptic responses following rapid stimulation of excitatory synapses and is thought to occur during learning. Kindling involves the repeated occurrence of a spike train known as the afterdischarge (AD) until seizure susceptibility is permanently altered. The significant synaptic potentiation that accompanies the AD cannot be enhanced further by LTP stimulation, suggesting the possibility of a common cellular mechanism. Evidence now indicates that protein kinase C (PKC) activity is involved in the maintenance or expression of LTP. The proposed studies will test the hypothesis that LTP and the first AD in the kindling process differ only in the degree of PKC activation. Central to this hypothesis is the assumption that PKC activity is not enhanced further by the repeated occurrence of an AD and, therefore, cannot account for the transition to the permanently kindled state. Experiments outlined under the first specific aim will assess the similarities and differences in PKC activity throughout the development and decay of synaptic potentiation elicited by LTP and AD stimulation. Experiments outlined under the second specific aim will evaluate the similarity of cellular mechanisms recruited during LTP and AD potentiation by interrupting PKC activation at sequential steps in the signal transduction pathway. In general, these experiments will be conducted in the awake, unrestrained rat, and where necessary, will be complemented by studies using an anesthetized or hippocampal slice preparation. Synaptic potentiation will be defined by a proportional change in the slope of the excitatory postsynaptic potential and in the amplitude of the population spike. PKC activity will be measured directly in membrane and cytosol fractions as the difference in activity in the presence or absence of phosphatidylserine. The results of these experiments will advance our understanding of cellular events that occur during the transition from adaptive (LTP) to pathophysiological (kindling) changes in synaptic transmission in the alert, unrestrained animal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH045961-03
Application #
3475398
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1991-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Graduate Hospital (Philadelphia)
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19146