Knowledge of the mechanisms that underlie activity-dependent neural plasticity is integral to understanding both normal and impaired memory function. The overall goal of the experiments proposed in this grant application is to study parameters critical for the induction and biochemical processes that underlie the maintenance and expression of long-term depression (LTD) of synaptic strength of glutamatergic synapses in the adult hippocampus in vivo. Research with formal models of learning and memory has shown that synaptic strength must have the capacity to both decrease and increase in a use-dependent manner for successful simulation of these cognitive processes. A common paradigm for inducing LTD is the delivery of prolonged low-frequency stimulation to the afferent pathway. However, LTD induced in such a fashion has been found to occur only in in vitro preparations using tissue from young animals. We recently have demonstrated that repeated paired-pulse stimulation of the commissural pathway reliably induces robust LTD of the commissural input to CA1 pyramidal cells in the adult hippocampus in vivo. Subsequent experiments have revealed that the induction of LTD by paired-pulse stimulation is dependent on N-methyl-D-aspartate (NMDA) receptor activation and, temporally overlapping, inhibitory input to the postsynaptic cell target mediated by activation of gamma-amino-butyric acid A (GABAA) receptors. If GABAergic inhibition is weak or absent during excitatory activation, then LTD fails to develop.
The first aim of the present proposal is to test whether or not the degree of GABAergic inhibition during paired-pulse stimulation controls the effectiveness of a train of paired pulses to induce LTD in the adult hippocampus in vivo. The mechanisms that underlie the maintenance and expression of LTD induced by paired-pulse stimulation currently are unknown. Differential activation of protein kinases and phosphatases commonly is thought to play a critical role in regulating bidirectional activity-dependent synaptic plasticity. The second and the third aim of the present proposal therefore is to examine in the adult hippocampus in vivo changes in protein phosphatase and protein kinase activity, respectively, in association with LTD induced by paired-pulse stimulation. The proposed experiments involve a rare combination of electrophysiological, pharmacological, and biochemical techniques to gain insight into the mechanisms that underlie activity-dependent neural plasticity in the intact adult brain.
