Long-term depression in the CNS

Key Points Long-term depression (LTD) encompasses a family of synaptic plasticity mechanisms that can be triggered by the synaptic or pharmacological activation of glutamate receptors — in particular NMDARs ( N -methyl- D -aspartate receptors) and metabotropic glutamate receptors (mGluRs) — or receptors for other neurotransmitters. LTD is expressed by a long-lasting decrease in the efficiency of synaptic transmission, in particular synaptic transmission that is mediated by the synaptic activation of AMPARs (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors). It may involve presynaptic and postsynaptic mechanisms. Complex signalling cascades link the induction of LTD to its expression. The cascades involve Ca 2+ sensors, protein–protein interactions, protein kinases and phosphatases, proteases and other signalling molecules. Historically, a lack of specific inhibitors for LTD has hampered efforts to specify its functional role. The recent development of interference peptide inhibitors targeted at the carboxyl tail of the AMPAR subunit GluA2 subunit has proven important in specifying the functional roles of LTD. LTD has diverse roles in cognition, particularly in some forms of learning and memory and in circumstances in which a flexible response is required. LTD also seems to be involved in pathological states, including drug addiction, mental retardation and neurodegenerative diseases such as Alzheimer's disease. In this comprehensive Review, Collingridge and colleagues describe the mechanisms underlying the induction and expression of various forms of long-term depression (LTD), and discuss the role of LTD in learning and memory as well as in various pathological processes. Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs ( N -methyl- D -aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of som