Cellular and biochemical mechanisms of long-term potentiation and homosynaptic long-term depression

Experience-dependent modifications of the brain, such as those that occur during memory formation and development, are believed to occur by bidirectional changes in the strength of synapses between neurons. Two model systems for synaptic change are long-term potentiation (LTP) and long-term depression (LTD). Two crucial questions are (1) whether LTP and LTD are related to naturally occurring synaptic plasticity, and (2) what are the biochemical mechanisms that are responsible for altering synaptic strength.; The role of LTP in naturally occurring plasticity was examined in the visual cortex. In this system, visual experience plays a crucial role in the establishment of functional connections during a "critical period" of early postnatal development. We discovered a form of LTP in rat visual cortex which exhibits a developmental decline that closely correlates with the decline in naturally occurring plasticity during the critical period. Furthermore, this decline in LTP, like the termination of the critical period, can be delayed by dark-rearing the animals. These results suggest that LTP-like mechanisms could account for developmentally regulated synaptic changes in the visual cortex.; The biochemical mechanisms that underlie LTD expression were investigated in rat hippocampal slices. Conventional induction protocols, using electrical stimulation, are not suitable for biochemical studies because only a small fraction of synapses are modified. To overcome this problem, I developed a novel method to produce LTD in a large population of synapses. Brief bath application of N-methyl- scD-aspartate (NMDA) was sufficient to produce a form of LTD, termed "chemLTD". We found that chemLTD is associated with a selective and persistent dephosphorylation of GluR1, one of the subunits of' AMPA-type glutamate receptors, at the site phosphorylated by cAMP-dependent protein kinase (Ser-845). We propose that changes in synaptic strength in the brain are expressed, in part, as alterations in the phosphorylation state of AMPA receptors.