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MINIREVIEW PROLOGUE THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 290, NO. 48, pp. 28594 –28595, November 27, 2015 © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
Thematic Minireview Series: Molecular Mechanisms of Synaptic Plasticity* Published, JBC Papers in Press, October 9, 2015, DOI 10.1074/jbc.R115.696468
Roger J. Colbran1 From the Department of Molecular Physiology & Biophysics, The Vanderbilt Brain Institute, and The Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
The human brain contains ⬃86 billion neurons, which are precisely organized in specific brain regions and nuclei. High fidelity synaptic communication between subsets of neurons in specific circuits is required for most human behaviors, and is often disrupted in neuropsychiatric disorders. The presynaptic axon terminals of one neuron release neurotransmitters that activate receptors on multiple postsynaptic neuron targets to induce electrical and chemical responses. Typically, postsynaptic neurons integrate signals from multiple presynaptic neurons at thousands of synaptic inputs to control downstream communication to the next neuron in the circuit. Importantly, the strength (or efficiency) of signal transmission at each synapse can be modulated on time scales ranging up to the lifetime of the organism. This “synaptic plasticity” leads to changes in overall neuronal circuit activity, resulting in behavioral modifications. This series of minireviews will focus on recent advances in our understanding of the molecular and cellular mechanisms that control synaptic plasticity.
Synaptic plasticity has been most intensively studied at synapses that release glutamate, the major excitatory neurotransmitter in the mammalian brain. Glutamatergic terminals typically connect to postsynaptic “spines,” morphologically diverse membrane protrusions, ⬃1 m in diameter, that decorate complex dendritic projections from postsynaptic cell bodies (reviewed in Ref. 1). A narrow neck between the heads of mature spines and the main dendritic shaft represents a significant electrical and chemical barrier to the communication of electrical and chemical changes between the two subcellular compartments. Dendritic spines are enriched in F-actin and are marked by an electron-dense postsynaptic density juxtaposed to the presynaptic terminal, which contains multiple glutamate receptor subtypes, ion channels, and signaling proteins. Postmortem studies of patients with diverse neurogenetic, neurodevelopmental, and neurodegenerative disorders have revealed abnormal dendritic spine morphology in various brain regions (2). Similar morphological changes can be recapitulated
* This
work was supported by National Institutes of Health Grants R01MH063232 and R01-NS078291 (to R. J. C.). The author declares that he has no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. 1 To whom correspondence should be addressed: Rm. 702, Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Tel.: 615936-1630; Fax: 615-322-7236; E-mail: [email protected].
28594 JOURNAL OF BIOLOGICAL CHEMISTRY
in animal models of several disorders and are typically accompanied by functional deficits in synaptic transmission and/ or synaptic plasticity. Consequently, molecular mechanisms underlying functional and morphological synaptic plasticity have been intensively studied for decades. Normal glutamatergic synaptic transmission is mediated by Na⫹ influx through AMPA-type glutamate receptors, and synaptic plasticity involves sustained changes in the activity of synaptic AMPA receptors (3, 4). In general, short bursts of intense (e.g. high frequency) synaptic stimulation result in Ca2⫹ influx via NMDA-type glutamate receptors to enhance AMPA receptor-mediated synaptic transmission, a process termed longterm potentiation (LTP).2 More prolonged periods of less intense stimulation often result in long-term depression (LTD) of synaptic transmission. Interestingly, different forms of LTD can be induced by activation of either NMDA receptors to induce postsynaptic Ca2⫹ influx or metabotropic glutamate receptors to induce Ca2⫹ release from intracellular stores. Thus, the postsynaptic Ca2⫹ signaling protein networks must be precisely tuned to induce distinct responses to different patterns and sources of postsynaptic Ca2⫹ transients. Moreover, because single synapses are capable of LTP or LTD depending on the pattern of stimulation at the corresponding presynaptic terminal, leaving nearby synapses unaltered, these Ca2⫹-dependent pathways must also be tightly compartmentalized between spines and within individual spines. Over the last couple of decades, it has become clear that postsynaptic Ca2⫹ signals required for synaptic plasticity regulate almost all basic cell biological processes. The highly abundant calcium/calmodulin-dependent protein kinase II (CaMKII) is central to many synaptic plasticity mechanisms. The unique dodecameric holoenzyme structure of CaMKII is required for a complex regulatory mechanism involving Ca2⫹/ calmodulin-dependent activation and inter-subunit autophosphorylation at Thr-286 that confers tight sensitivity to the frequency of Ca2⫹ transients. Normal LTP induction requires both Thr-286 autophosphorylation and the precise synaptic targeting of CaMKII via a direct interaction with the GluN2B subunit of the NMDA receptor. Interestingly, recent studies have shown that CaMKII also plays important roles in LTD. Mechanisms underlying the roles of CaMKII in synaptic plasticity have been recently reviewed in detail (5– 8). However, beyond the roles for CaMKII, various forms of functional synaptic plasticity are typically associated with diverse posttranslational modifications that regulate the activity and subcellular trafficking of synaptic glutamate receptor subunits, as reviewed by Roche and colleagues (9) in the first minireview in this series. In the second minireview in this series, Woolfrey and Dell’Acqua (10) review the mechanisms that coordinate the precise actions of postsynaptic protein kinases and protein phosphatases on glutamate receptors and other postsynaptic proteins. Changes in size and shape of dendritic spines and/ 2
The abbreviations used are: LTP, long-term potentiation; LTD, long-term depression; CaMKII, calcium/calmodulin-dependent protein kinase II.
VOLUME 290 • NUMBER 48 • NOVEMBER 27, 2015
MINIREVIEW: Synaptic Plasticity Mechanisms or postsynaptic densities associated with synaptic plasticity involve precise changes in the F-actin cytoskeleton, as reviewed by Spence and Soderling (11) in the third minireview in this series. Finally, persistent behavioral modification, such as a lifetime memory, requires the long-term stability of synaptic plasticity in the face of normal protein turnover, and this involves synapse-specific modulation of protein synthesis and degradation, as reviewed by Alvarez-Castelao and Schuman (12) in the fourth minireview in this series. It can be anticipated that future studies of synaptic plasticity mechanisms will reveal new strategies for treatment of a wide range of neuropsychiatric disorders associated with disruptions in these signaling mechanisms. References 1. Bourne, J. N., and Harris, K. M. (2008) Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47– 67 2. Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J. E., and Woolfrey, K. M. (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat. Neurosci. 14, 285–293 3. Kessels, H. W., and Malinow, R. (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340 –350
NOVEMBER 27, 2015 • VOLUME 290 • NUMBER 48
4. Malinow, R., and Malenka, R. C. (2002) AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 5. Hell, J. W. (2014) CaMKII: claiming center stage in postsynaptic function and organization. Neuron 81, 249 –265 6. Lisman, J., Yasuda, R., and Raghavachari, S. (2012) Mechanisms of CaMKII action in long-term potentiation. Nat. Rev. Neurosci. 13, 169 –182 7. Shonesy, B. C., Jalan-Sakrikar, N., Cavener, V. S., and Colbran, R. J. (2014) CaMKII: a molecular substrate for synaptic plasticity and memory. Prog. Mol. Biol. Transl. Sci. 122, 61– 87 8. Coultrap, S. J., and Bayer, K. U. (2012) CaMKII regulation in information processing and storage. Trends Neurosci. 35, 607– 618 9. Lussier, M. P., Sanz-Clemente, A., and Roche, K. W. (2015) Dynamic regulation of NMDA and AMPA receptors by posttranslational modifications. J. Biol. Chem. 48, 28596 –28603 10. Woolfrey, K. M., and Dell’Acqua, M. L. (2015) Coordination of protein phosphorylation and dephosphorylation in synaptic plasticity. J. Biol. Chem. 48, 28604 –28612 11. Spence, E. F., and Soderling, S. H. (2015) Actin out: regulation of the synaptic cytoskeleton. J. Biol. Chem. 48, 28613–28622 12. Alvarez-Castelao, B., and Schuman, E. M. (2015) The regulation of synaptic protein turnover. J. Biol. Chem. 48, 28623–28630
JOURNAL OF BIOLOGICAL CHEMISTRY
28595
MINIREVIEW PROLOGUE THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 290, NO. 48, pp. 28594 –28595, November 27, 2015 © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
Thematic Minireview Series: Molecular Mechanisms of Synaptic Plasticity* Published, JBC Papers in Press, October 9, 2015, DOI 10.1074/jbc.R115.696468
Roger J. Colbran1 From the Department of Molecular Physiology & Biophysics, The Vanderbilt Brain Institute, and The Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
The human brain contains ⬃86 billion neurons, which are precisely organized in specific brain regions and nuclei. High fidelity synaptic communication between subsets of neurons in specific circuits is required for most human behaviors, and is often disrupted in neuropsychiatric disorders. The presynaptic axon terminals of one neuron release neurotransmitters that activate receptors on multiple postsynaptic neuron targets to induce electrical and chemical responses. Typically, postsynaptic neurons integrate signals from multiple presynaptic neurons at thousands of synaptic inputs to control downstream communication to the next neuron in the circuit. Importantly, the strength (or efficiency) of signal transmission at each synapse can be modulated on time scales ranging up to the lifetime of the organism. This “synaptic plasticity” leads to changes in overall neuronal circuit activity, resulting in behavioral modifications. This series of minireviews will focus on recent advances in our understanding of the molecular and cellular mechanisms that control synaptic plasticity.
Synaptic plasticity has been most intensively studied at synapses that release glutamate, the major excitatory neurotransmitter in the mammalian brain. Glutamatergic terminals typically connect to postsynaptic “spines,” morphologically diverse membrane protrusions, ⬃1 m in diameter, that decorate complex dendritic projections from postsynaptic cell bodies (reviewed in Ref. 1). A narrow neck between the heads of mature spines and the main dendritic shaft represents a significant electrical and chemical barrier to the communication of electrical and chemical changes between the two subcellular compartments. Dendritic spines are enriched in F-actin and are marked by an electron-dense postsynaptic density juxtaposed to the presynaptic terminal, which contains multiple glutamate receptor subtypes, ion channels, and signaling proteins. Postmortem studies of patients with diverse neurogenetic, neurodevelopmental, and neurodegenerative disorders have revealed abnormal dendritic spine morphology in various brain regions (2). Similar morphological changes can be recapitulated
* This
work was supported by National Institutes of Health Grants R01MH063232 and R01-NS078291 (to R. J. C.). The author declares that he has no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. 1 To whom correspondence should be addressed: Rm. 702, Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Tel.: 615936-1630; Fax: 615-322-7236; E-mail: [email protected].
28594 JOURNAL OF BIOLOGICAL CHEMISTRY
in animal models of several disorders and are typically accompanied by functional deficits in synaptic transmission and/ or synaptic plasticity. Consequently, molecular mechanisms underlying functional and morphological synaptic plasticity have been intensively studied for decades. Normal glutamatergic synaptic transmission is mediated by Na⫹ influx through AMPA-type glutamate receptors, and synaptic plasticity involves sustained changes in the activity of synaptic AMPA receptors (3, 4). In general, short bursts of intense (e.g. high frequency) synaptic stimulation result in Ca2⫹ influx via NMDA-type glutamate receptors to enhance AMPA receptor-mediated synaptic transmission, a process termed longterm potentiation (LTP).2 More prolonged periods of less intense stimulation often result in long-term depression (LTD) of synaptic transmission. Interestingly, different forms of LTD can be induced by activation of either NMDA receptors to induce postsynaptic Ca2⫹ influx or metabotropic glutamate receptors to induce Ca2⫹ release from intracellular stores. Thus, the postsynaptic Ca2⫹ signaling protein networks must be precisely tuned to induce distinct responses to different patterns and sources of postsynaptic Ca2⫹ transients. Moreover, because single synapses are capable of LTP or LTD depending on the pattern of stimulation at the corresponding presynaptic terminal, leaving nearby synapses unaltered, these Ca2⫹-dependent pathways must also be tightly compartmentalized between spines and within individual spines. Over the last couple of decades, it has become clear that postsynaptic Ca2⫹ signals required for synaptic plasticity regulate almost all basic cell biological processes. The highly abundant calcium/calmodulin-dependent protein kinase II (CaMKII) is central to many synaptic plasticity mechanisms. The unique dodecameric holoenzyme structure of CaMKII is required for a complex regulatory mechanism involving Ca2⫹/ calmodulin-dependent activation and inter-subunit autophosphorylation at Thr-286 that confers tight sensitivity to the frequency of Ca2⫹ transients. Normal LTP induction requires both Thr-286 autophosphorylation and the precise synaptic targeting of CaMKII via a direct interaction with the GluN2B subunit of the NMDA receptor. Interestingly, recent studies have shown that CaMKII also plays important roles in LTD. Mechanisms underlying the roles of CaMKII in synaptic plasticity have been recently reviewed in detail (5– 8). However, beyond the roles for CaMKII, various forms of functional synaptic plasticity are typically associated with diverse posttranslational modifications that regulate the activity and subcellular trafficking of synaptic glutamate receptor subunits, as reviewed by Roche and colleagues (9) in the first minireview in this series. In the second minireview in this series, Woolfrey and Dell’Acqua (10) review the mechanisms that coordinate the precise actions of postsynaptic protein kinases and protein phosphatases on glutamate receptors and other postsynaptic proteins. Changes in size and shape of dendritic spines and/ 2
The abbreviations used are: LTP, long-term potentiation; LTD, long-term depression; CaMKII, calcium/calmodulin-dependent protein kinase II.
VOLUME 290 • NUMBER 48 • NOVEMBER 27, 2015
MINIREVIEW: Synaptic Plasticity Mechanisms or postsynaptic densities associated with synaptic plasticity involve precise changes in the F-actin cytoskeleton, as reviewed by Spence and Soderling (11) in the third minireview in this series. Finally, persistent behavioral modification, such as a lifetime memory, requires the long-term stability of synaptic plasticity in the face of normal protein turnover, and this involves synapse-specific modulation of protein synthesis and degradation, as reviewed by Alvarez-Castelao and Schuman (12) in the fourth minireview in this series. It can be anticipated that future studies of synaptic plasticity mechanisms will reveal new strategies for treatment of a wide range of neuropsychiatric disorders associated with disruptions in these signaling mechanisms. References 1. Bourne, J. N., and Harris, K. M. (2008) Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47– 67 2. Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J. E., and Woolfrey, K. M. (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat. Neurosci. 14, 285–293 3. Kessels, H. W., and Malinow, R. (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340 –350
NOVEMBER 27, 2015 • VOLUME 290 • NUMBER 48
4. Malinow, R., and Malenka, R. C. (2002) AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 5. Hell, J. W. (2014) CaMKII: claiming center stage in postsynaptic function and organization. Neuron 81, 249 –265 6. Lisman, J., Yasuda, R., and Raghavachari, S. (2012) Mechanisms of CaMKII action in long-term potentiation. Nat. Rev. Neurosci. 13, 169 –182 7. Shonesy, B. C., Jalan-Sakrikar, N., Cavener, V. S., and Colbran, R. J. (2014) CaMKII: a molecular substrate for synaptic plasticity and memory. Prog. Mol. Biol. Transl. Sci. 122, 61– 87 8. Coultrap, S. J., and Bayer, K. U. (2012) CaMKII regulation in information processing and storage. Trends Neurosci. 35, 607– 618 9. Lussier, M. P., Sanz-Clemente, A., and Roche, K. W. (2015) Dynamic regulation of NMDA and AMPA receptors by posttranslational modifications. J. Biol. Chem. 48, 28596 –28603 10. Woolfrey, K. M., and Dell’Acqua, M. L. (2015) Coordination of protein phosphorylation and dephosphorylation in synaptic plasticity. J. Biol. Chem. 48, 28604 –28612 11. Spence, E. F., and Soderling, S. H. (2015) Actin out: regulation of the synaptic cytoskeleton. J. Biol. Chem. 48, 28613–28622 12. Alvarez-Castelao, B., and Schuman, E. M. (2015) The regulation of synaptic protein turnover. J. Biol. Chem. 48, 28623–28630
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