2000husi - 2000 Nature America Inc....

Info iconThis preview shows pages 1–2. Sign up to view the full content.

View Full Document Right Arrow Icon
articles nature neuroscience volume 3 no 7 july 2000 661 A prevailing cellular model of learning involves modification of synapse strength, induced by patterns of neuronal activity dur- ing training, which encodes information in neural networks 1,2 . Understanding the molecular mechanisms used by synapses to detect altered patterns of firing, and how signaling cascades then change the strength of synaptic transmission, may provide basic insights into this model and illuminate pathological mechanisms that occur in human learning impairments and other psychiatric disorders 3 . Considerable attention has focused on the NMDA subtype of glutamate receptor 4 because its blockade in the hip- pocampus impairs both synaptic plasticity and learning 1 . This receptor channel, which allows calcium influx into the postsy- naptic spine, regulates kinases, phosphatases and other enzymes, which then regulate AMPA ( α -amino-3-hydroxy-5-methyl-4- isoxasole-4-propionic acid) glutamate receptors (AMPARs), spine cytoskeletal changes, translation, transcription and other events. These diverse actions indicate the NMDAR couples to multiple intracellular signaling pathways. Moreover, in a physiological set- ting, these signals must be subtly integrated, as shown by elec- trophysiological studies in CA3–CA1 synapses of the hippocampus, where low-frequency synaptic stimulation results in NMDAR-dependent long-term depression (LTD) and higher frequencies in long-term potentiation (LTP) of synaptic strength 2 . LTP comprises a series of temporally distinct processes that can broadly be separated into ‘induction’ and ‘maintenance’ phas- es. The induction phase includes the train of stimuli that acti- vate the NMDA receptor, which lasts for seconds or less, and a period of minutes during which second messenger pathways act, leading to a new stable level of synapse strength in the mainte- nance phase. Unlike the induction phase, the maintenance phase is resistant to inhibitors of second messengers, such as kinases and phosphatases, although it is sensitive to inhibitors of RNA and protein synthesis for the first two to three hours, indicating a role for new gene expression 1,2 . In parallel with this require- ment for gene expression in the late phases of LTP, the NMDAR is required for transcriptional activation and dendritic trafficking of mRNAs and proteins such as Arg3.1/Arc and Homer/Vesl. A recent review 5 of the molecular mechanisms of LTP highlighted the large number of implicated molecules and the lack of a sat- isfying model. In addition to neurotransmitter receptors and multiple signaling proteins, this list of molecules included adhe- sion and structural proteins. An approach to the problem of understanding the molecular basis of LTP and its signaling path- ways is to combine a functional genetic and pharmacological dis- section with structural analysis of the organization of synaptic molecules.
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Image of page 2
This is the end of the preview. Sign up to access the rest of the document.

Page1 / 10

2000husi - 2000 Nature America Inc....

This preview shows document pages 1 - 2. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online