Abstract
A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights. Multiple mechanisms for producing such changes exist, of which NMDA-receptor–dependent long-term potentiation (LTP) is the most widely studied. Curiously, the relatively simple hypothesis that LTP plays a role in learning and memory has proven difficult to test. A current experimental strategy is to generate genetically altered mice with mutations in genes thought to be involved in LTP and assess the effects of these mutations both on LTP and animal behavior[1,2]. A difficulty associated with these approaches has been that they are not temporally or spatially refined. To alleviate this problem, Dr. Isabelle Mansuy and colleagues used an inducible and reversible transgene expression system in which transgene expression could be controlled on a week-to-week timescale to assess the effects of genetic reduction of the activity of a protein phosphatase known as calcineurin or PP2B in adult mouse forebrain[3,4].
Highlights
A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights
Two key sets of pharmacological studies, two by Mulkey and Malenka[5,6] demonstrating a requirement for phosphatase activity in weakening synaptic strength, and two by Blitzer et al.[7,8] demonstrating that protein kinase A (PKA) is required for long-term potentiation (LTP) induction in part to suppress phosphatase activity, have fueled interest in these enzymes
Strong synaptic activity would lead to large increases in intracellular calcium, resulting in activation of CaMKII, a key kinase required for LTP induction, and protein kinase A (PKA)
Summary
A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights. Phosphorylation/dephosphorylation plays a critical role in the induction of LTP, and pharmacological and genetic approaches have begun to tease out the various roles played by specific kinases. Phosphatases, once thought to play a somewhat mundane, accessory role, are starting to receive more attention as active mediators and regulators of synaptic plasticity[9].
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