Scientific Understanding of Consciousness
Plasticity of Synapses
Science 4 November 2011: Vol. 334 no. 6056 pp. 623-628
The Cell Biology of Synaptic Plasticity
Victoria M. Ho1, Ji-Ann Lee2, Kelsey C. Martin2,3,4
1Interdepartmental Program in Neurosciences, University of California–Los Angeles (UCLA), BSRB 390B, 615 Charles E. Young Drive South, Los Angeles, CA 90095–1737, USA.
2Department of Biological Chemistry, UCLA, BSRB 310, 615 Charles E. Young Drive South, Los Angeles, CA 90095–1737, USA.
3Department of Psychiatry and Biobehavioral Sciences, UCLA, BSRB 390B, 615 Charles E. Young Drive South, Los Angeles, CA 90095–1737, USA.
4Brain Research Institute, UCLA, BSRB 390B, 615 Charles E. Young Drive South, Los Angeles, CA 90095–1737, USA.
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.
The circuitry of the human brain is composed of a trillion (1012) neurons and a quadrillion (1015) synapses, whose connectivity underlies all human perception, emotion, thought, and behavior. Studies in a range of species have revealed that the overall structure of the nervous system is genetically hard-wired but that neural circuits undergo extensive sculpting and rewiring in response to a variety of stimuli. This process of experience-dependent changes in synaptic connectivity is called synaptic plasticity.
Studies of synaptic plasticity have begun to detail the molecular mechanisms that underlie these synaptic changes. This research has examined a variety of cell biological processes, including synaptic vesicle release and recycling, neurotransmitter receptor trafficking, cell adhesion, and stimulus-induced changes in gene expression within neurons. Taken together, these studies have provided an initial molecular biological understanding of how nature and nurture combine to determine our identities
Here we focus on long-lasting forms of plasticity that underlie learning and memory. We consider, in turn, each component of the synapse: the presynaptic compartment, the postsynaptic compartment, and the synaptic cleft, and discuss processes that undergo activity-dependent modifications to alter synaptic efficacy. Long-lasting changes in synaptic connectivity require new RNA and/or protein synthesis, and we discuss how gene expression is regulated within neurons. We concentrate on studies of learning-related plasticity at excitatory chemical synapses in the rodent hippocampus because these provide extensive evidence for the cell biological mechanisms of plasticity in the vertebrate brain. Space constraints prevent us from addressing any single mechanism in depth; instead, our aim is to provide a framework for understanding the cell biology of synaptic plasticity.
Hippocampal Synaptic Plasticity
The successful study of the cell biology of synaptic plasticity requires a tractable experimental model system. Ideally, such a model should consist of a defined population of identifiable neurons and be amenable to electrophysiological, genetic, and molecular cell biological manipulations. A well-studied model system for studying plasticity in the adult vertebrate nervous system is the rodent hippocampus. Critical for memory formation, the anatomy of the hippocampus renders it particularly suitable for electrophysiological investigation. It consists of three sequential synaptic pathways (perforant, mossy fiber, and Schaffer collateral pathways), each with discrete cell body layers and axonal and dendritic projections. Synaptic plasticity has been studied in all three hippocampal pathways. Distinct stimuli elicit changes in synaptic efficacy; high-frequency stimuli produce synaptic strengthening called long-term potentiation (LTP), and low-frequency stimulation produces synaptic weakening, called long-term depression (LTD). LTP and LTD can also be produced by spike timing–dependent plasticity, in which the relative timing of pre- and postsynaptic spikes leads to changes in synaptic strength. Different patterns of stimulation elicit changes in synaptic strength that persist over various time domains, with long-lasting forms, but not short-term forms, requiring new RNA and protein synthesis.
Presynaptic Mechanisms of Plasticity
Communication at chemical synapses involves the release of neurotransmitter from the presynaptic terminal, diffusion across the cleft, and binding to postsynaptic receptors. Chemical neurotransmission is rapid (occurring in milliseconds) and highly regulated. The presynaptic terminal contains synaptic vesicles filled with neurotransmitter and a dense matrix of cytoskeleton and scaffolding proteins at the site of release, the active zone. Varying the probability of neurotransmitter release provides one mechanism for altering synaptic strength during neuronal plasticity.
Postsynaptic Mechanisms of Plasticity
Most principle neurons in the brain are studded with membrane protuberances called dendritic spines, which are the postsynaptic compartments. Spines are heterogeneous in shape. but consist of a bulbous head and a thinner neck that connects the spine to the dendritic shaft; the size of the spine head and the volume of the spine correlate with synaptic strength, with large spine heads containing more neurotransmitter receptors, reflecting greater synaptic strength. Spines serve as compartmentalized signaling units, and the number and shape of spines change during synaptic plasticity.
Trans-Synaptic Signaling; the Synaptic Cleft
The synaptic cleft is a ~20-nm junction between the pre- and postsynaptic compartments, consisting of a space through which neurotransmitters diffuse to bind postsynaptic receptors, as well as a network of cell adhesion molecules (CAMs) that keeps the synapse together. These adhesive interactions are so strong that it is impossible to separate intact pre- from postsynaptic compartments biochemically.
The Tripartite Synapse: Glia and Synaptic Plasticity
Once thought of as the “support cells” of the nervous systems, glial cells are now considered essential partners in synapse formation, synaptic transmission, and plasticity. Astrocytes surround the synapse, forming a “tripartite synapse,” composed of neuronal pre- and postsynaptic compartments as well as surrounding astrocytes. Synaptically localized glia release neuroactive molecules that influence neuronal communication. For example, release of d-serine (a coactivator of the NMDA receptor) from glia is required for LTP of hippocampal Schaffer collateral synapses. Ephrin and Eph receptor signaling between neurons and glia regulates the uptake of glutamate through glial glutamate transporters and thereby affects neurotransmission and synaptic plasticity. The release of lactate from astrocytes and uptake by neurons has also been reported to be required for long-term hippocampal memory and plasticity.
Regulating Gene Expression Within Neurons During Plasticity
Signaling from synapse to nucleus to regulate transcription. Long-lasting forms of synaptic plasticity, such as those underlying long-term memory, require new RNA synthesis. This indicates that synaptic signals must be relayed to the nucleus to regulate transcription. Synapse-to-nucleus signaling poses a unique set of challenges in neurons, where the distance between the synapse and nucleus can be appreciable. Neurons are specialized for rapid communication between compartments via electrochemical signaling, with depolarization at the synaptic terminal leading to depolarization at the soma in less than a millisecond. Calcium influx can occur through voltage- and ligand-gated ion channels. Cytosolic calcium can also be released from intracellular pools following activation of Gq-coupled receptors such as metabotropic GluRs (mGluRs). Each route of calcium influx induces different programs of gene induction
Local Protein Synthesis
Despite requiring new transcription, LTP and LTD can occur in a spatially restricted manner, raising the question of how gene expression in neurons can be limited to subsets of synapses and not generalized to the entire cell. One way of locally changing the proteome in neurons is through regulated translation of localized mRNAs
Studies of mRNA localization have led to the identification of cis-acting RNA elements that bind to RNA-binding proteins to undergo export from the soma into the dendrite
Local Protein Degradation
The local proteome is regulated not only by local translation but also by protein degradation through the ubiquitin proteasome system. Both protein synthesis and degradation are required for the maintenance of late-phase LTP, suggesting that protein degradation is needed to counterbalance protein synthesis during plasticity. Like local translation, protein degradation can be regulated within dendrites. Ubiquitin and proteasomal subunits have been found in dendrites and at synapses, and stimulation of hippocampal neurons triggers proteasome-dependent changes in the composition of PSD proteins. Activity-dependent degradation involves redistribution of proteasomes from dendritic shafts to spines. Notably, the ubiquitin proteasome pathway alters AMPAR trafficking and degradation at synapses during plasticity.
As the above examples illustrate, cell biological approaches have provided a detailed understanding of many aspects of activity-dependent plasticity. By focusing on molecular processes occurring within individual neurons and subcellular compartments, we now understand specific processes that are modulated by experience to change synaptic strength. These involve alterations in neurotransmitter release, trans-synaptic signaling, postsynaptic receptor dynamics, and gene expression within neurons. Distinct plasticity mechanisms are used at different types of synapses. For instance, LTP at mossy fiber synapses occurs primarily through presynaptic changes, whereas LTP at Schaffer collateral synapses occurs mostly through postsynaptic mechanisms. The end result of many of the processes we have described is to regulate the concentration of glutamate receptors, indicating that this is a major postsynaptic determinant of synaptic strength during plasticity.
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