LONG-TERM POTENTIATION IN DEVELOPING HIPPOCAMPUS

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Long-term potentiation (LTP) is the sustained increase in synaptic strength that follows brief stimulation of afferent fibers. In adult animals, LTP is a model of the physical changes that occur in learning and memory. In immature animals, LTP may also underlie normal developmental processes such as the brain's susceptibility to environmental modification during "critical periods" and pathologic processes such as epileptogenesis. In contrast to adults, developing animals undergo rapid maturational changes in the neural elements crucial for the genesis of LTP. Thus mechanisms of LTP during development may differ considerably from those in adults. The goal of this research is to elucidate mechanisms of LTP in developing hippocampus. Extracellular recordings in hippocampal slices from rats 1-20 days will be used to provide a detailed survey of the developmental onset of LTP in three pathways: perforant path-dentate gyrus; mossy fiber-CA3; commissural/associational CA3. Key developmental stages and pathways thus identified will be tested for NMDA-dependence using selective blockade of NMDA or non-NMDA receptors. Intracellular recordings will be used to further examine the cellular mechanisms of potentiation of the EPSP and changes in the firing threshold (E-S potentiation). Short term changes in inhibitory efficacy will be examined using extracellularly monitored paired pulse depression and intracellularly recorded changes in slope conductance of IPSPs following non-potentiating stimulation. Long-term changes in plasticity of inhibition will be assessed by intracellular measurements of changes in IPSP following LTP induction. The role of calcium will be examined by post synaptic calcium chelation and activation and inhibition of calcium-dependent protein kinases. Finally, developmental changes in NMDA receptor distribution and PKC activation as they relate to LTP will be studied using quantitative autoradiography. This systematic investigation of LTP in immature animals is based on mechanisms well-characterized in adults and is expected to yield novel information about synaptic plasticity during development.