doi: 10.1126/science.1209236.
The cell biology of synaptic plasticity
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- PMID: 22053042
- PMCID: PMC3286636
- DOI: 10.1126/science.1209236
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The cell biology of synaptic plasticity
Science.
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Abstract
Synaptic plasticity is the experience-dependent change in connectivity between neurons that is believed to underlie learning and memory. Here, we discuss the cellular and molecular processes that are altered when a neuron responds to external stimuli, and how these alterations lead to an increase or decrease in synaptic connectivity. Modification of synaptic components and changes in gene expression are necessary for many forms of plasticity. We focus on excitatory neurons in the mammalian hippocampus, one of the best-studied model systems of learning-related plasticity.
Figures
A. The rodent hippocampus can be dissected out and cut into transverse slices (B) preserving all three synaptic pathways. In the perforant pathway (purple), axons from the entorhinal cortex project to form synapses (red circles) on dendrites of dentate granule cells; in the mossy fiber pathway (green), dentate granule axons synapse on CA3 pyramidal neuron dendrites; and in the Schaffer collateral pathway (brown), CA3 axons synapse on CA1 dendrites. The dentate, CA3 and CA1 cell bodies form discrete somatic layers (dark blue lines), projecting axons and dendrites into defined regions. Electrodes can be used to stimulate axonal afferents and record from postsynaptic follower cells, as illustrated for the Schaffer collateral (CA3-CA1) pathway. Test stimuli elicit a stable synaptic response in the follower cell, measured as a excitatory post-synaptic potentials (EPSP, Ci). Trains of high frequency stimulation (HFS) or low frequency stimulation (LFS) to the axonal fibers produce sustained increases or decreases, respectively of the EPSP amplitude in response to subsequent test stimuli (C and D). These forms of plasticity are known as long-term potentiation (LTP) and long-term depression (LTD). Figure adapted from (56).
Neurons communicate with one another at chemical synapses. A) In this electron micrograph from area CA1 in adult rat hippocampus, the CA1 dendritic shaft is colorized in yellow, the spine neck and head in green, the presynaptic terminal in orange, and astroglial processes in blue. Scale bar, 0.5 μm. B) Three-dimensional reconstruction of an 8.5 μm long dendrite (yellow) with the PSDs labeled in red. Note the variation in spine and PSD size and shape. Scale cube, 0.5 μm3. Reproduced with permission from Bourne and Harris (57).
Presynaptic:
Neurotransmitter vesicle cycling. Neurotransmitter release starts with the filling of synaptic vesicles. Filled vesicles then dock and undergo priming at the active zone. Arrival of an action potential induces calcium influx through voltage-sensitive calcium channel (VSCC), which in turn triggers membrane fusion and exocytosis of the neurotransmitters. The synaptic vesicles are then recycled via local reuse (a; also called kiss and stay), fast recycling (b; also called kiss and run), or clathrin-mediated endocytosis (c). The efficacy of the neurotransmitter release can be regulated during plasticity as exemplified by the regulation of synapsin phosphorylation (1) and the regulation of RIM protein phosphorylation (2). Postsynaptic: AMPA receptor trafficking. Locally and somatically synthesized AMPARs enter a pool of endosomes that cycle constitutively and in an activity-dependent manner. During potentiation, greater receptor insertion (3) increases the concentration of AMPARs at the synapse, where they are anchored by interactions at the PSD. During synaptic depression, AMPARs are endocytosed (3). The preferential location of endocytosis and exocytosis is not precisely known, but probably occurs extrasynaptically. Within the plasma membrane, trafficking of AMPARs between the synapse and the point of insertion/removal occurs by lateral diffusion. Extrasynaptic movement of AMPARs increases with neuronal activity (4). Receptor trafficking is modulated by phosphorylation of AMPAR subunits (5), which influences interactions with scaffolding proteins. Trans-synaptic: Synaptic cell adhesion molecules. PSA-NCAM is increased following neuronal activity (6). Lightning bolts indicate activity-dependent processes.
Synaptic plasticity modifies gene expression at many levels. Strong stimulation of synapses triggers signals that are sent to the nucleus to modify RNA synthesis. Synaptic activity also modifies protein synthesis, and has been found to act at several key steps during translation: (1) Relief of repression, e.g. RISC-mediated repression; (2) Modification of translational initiation to allow 4E–4G interaction and recruitment of 40S; (3) Formation of the preinitiation complex; (4) Dephosphorylation of eEF2 to allow for catalysis of ribosome translocation during translational elongation. To counterbalance local protein synthesis, local protein degradation also occurs at synapses (5). Together, these regulated steps in protein addition and removal allow for rapid, spatially-restricted control of the synaptic proteome. Lightning bolts indicate activity-dependent processes. (Note: while local translation in dendrites is a well-accepted phenomenon, it has not been demonstrated to occur in spines. Also, the precise location of some of the translational machinery and regulatory steps depicted has not been identified.)
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