Protein Synthesis in Neurons

Abstract

Neurons are immensely complex cells whose morphology and physiology underpin our cognition. Achieving proper neuronal connections during development, as well as eliciting appropriate responses to environmental stimuli in the adult, requires precisely regulated protein synthesis. To meet these requirements, neurons have adapted regulatory mechanisms that act at every step in the process of producing functional proteins. Many of these mechanisms target messenger ribonucleic acid (mRNA)‐binding proteins and ribosomal subunits to regulate translational initiation. These mechanisms are especially concentrated at synapses, where they act to transform transient electrical signals into lasting functional modifications that are a basis for learning and memory. Misregulated synaptic protein synthesis contributes to several human cognitive changes including addiction, fragile X syndrome and autism.

Key Concepts:

  • Neurons exhibit extensive and compartmentalised arbours of axons and dendrites, which place unique demands on the timing and location of protein synthesis.

  • Growth cones are specialised structures that guide developing axons and dendrites to their targets. Extracellular guidance cues regulate local protein synthesis in growth cones to guide axons and dendrites to their destination.

  • Forming new memories requires protein synthesis during specific time intervals after learning.

  • In the adult brain, neurons rapidly communicate through specialised contacts called synapses. The strength of communication at a synapse can be modified as a function of its past use. These changes are mediated, in part, by the local protein synthesis at the synapse.

  • Biochemical networks called signal transduction pathways convert specific patterns of synaptic transmissions into new protein synthesis. Ribosomal and RNA‐binding proteins are common targets of these pathways.

  • Alterations of neuronal protein synthesis in humans can cause a variety of behavioural, cognitive and memory deficits.

Keywords: protein synthesis; neuron; translation; synapse; fragile X

Figure 1.

Post‐translational processing and trafficking of secreted and transmembrane proteins in neurons: (a) During and after translation, secreted and transmembrane proteins receive post‐translational modifications (text, left) as they pass through the endoplasmic reticulum (ER), Golgi apparatus and trans‐Golgi network (TGN). Finally, vesicles containing the proteins bud from the TGN and are transported to their final destination. Targeting mechanisms guide the vesicles to the axon or dendrites and then to the correct area within each where they are secreted or inserted into the plasma membrane. In a process called transcytosis (centre), some axonal membrane proteins are first inserted into the dendritic plasma membrane and then reinternalised and trafficked to the axon. (b) Transmembrane proteins, including neurotransmitter receptors, can also be removed from and inserted into the membrane at synapses. Stimulation changes the number of receptors at a synapse which determines the magnitude of synaptic transmissions. On the presynaptic side there are clear vesicles that contain conventional neurotransmitters (e.g. glutamate, GABA) as well as dense‐core vesicles that contain neuropeptides. (c) Many neuropeptides are produced by cleavage of a single large precursor called a prepropeptide in the Golgi and the TGN. Illustrated, a precursor called proopiomelanocortin (POMC) is cleaved up to 8 times to form up to 10 different neuropeptides. (From Castro and Morrison .). (d) As a transmembrane protein is translated, signal sequences in the protein cause it to cross the ER membrane in a certain orientation. Secreted proteins cross the ER membrane a single time. Multiple signal sequences can cause the protein to cross the ER membrane many times (not shown). Adapted from Lodish et al..

Figure 2.

In‐vitro models used to study protein synthesis in neurons: (a) Hippocampal slices are slabs of brain tissue cut from an area of the brain called the hippocampus. Stimulation of axons in the slice elicits synaptic transmission. Certain types of stimulation cause long‐term changes in the magnitude of future synaptic transmission. High‐frequency stimulation causes a long‐term increase in the magnitude of future transmission (plotted as percentage of baseline). Low‐frequency stimulation causes a long‐term decrease. Translation inhibitors can be applied to the slice to show that these long‐term changes require translation. (From Sawtell et al. .) (b) Neurons from the sea slug Aplysia can be dissected and arranged to form synapses in specific configurations. Here, a sensory neuron makes synapses with two motor neurons. This allows neurotransmitter to be applied to a single synapse, which is generally not possible in preparations of vertebrate neurons. The magnitude of synaptic transmission only increases at the synapse where neurotransmitter was applied (right). Translation inhibitors can be applied locally to show that persistence of this change requires local translation only at the activated synapse. (Neurons diagram from Martin et al. ; graphs from Casadio et al..) (c) Cells in the brain can be dissociated and grown as a single cell layer. This is useful for biochemical studies and for visualising the location of proteins and mRNAs in intact neurons. (d) Grinding up the brain and centrifuging the homogenate results in a subcellular fraction called synaptoneurosomes that is enriched in synaptic compartments. By courtesy of Anna Klintsova; http://www.itg.uiuc.edu/exhibits/gallery/pages/image‐49.htm. This fraction is useful for biochemical studies of synapses, but can be unreliable due to contamination with other cellular fragments.

Figure 3.

Signal transduction pathways that lead to translation and transcription in neurons. Extracellular ligands bind cell surface receptors coupled to cascades of molecular interactions that cause translation and transcription. Note that most pathways directly or indirectly target the initiation complex, formation of which is the rate‐limiting step in translation. The pathways illustrated are greatly simplified. A single type of receptor can activate many pathways and different pathways interact extensively. Each pathway ‘component’ is often a complex of subunits. After a pathway is activated, additional molecules are required to deactivate it as well as the transcription and translation that it triggers (not shown).

close

References

An JJ, Gharami K, Liao GY et al. (2008) Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134(1): 175–187.

Banko JL, Hou L, Poulin F, Sonenberg N and Klann E (2006) Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor‐dependent long‐term depression. Journal of Neuroscience 26(8): 2167–2173.

Bear MF, Huber KM and Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends in Neurosciences 27(7): 370–377.

Bourtchuladze R, Frenguelli B, Blendy J et al. (1994) Deficient long‐term memory in mice with a targeted mutation of the cAMP‐responsive element‐binding protein. Cell 79(1): 59–68.

Casadio A, Martin KC, Giustetto M et al. (1999) A transient, neuron‐wide form of CREB‐mediated long‐term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99(2): 221–237.

Castro MG and Morrison E (1997) Post‐translational processing of proopiomelanocortin in the pituitary and in the brain, Critical Reviews in Neurobiology 11(1): 35–57.

Christie SB, Akins MR, Schwob JE and Fallon JR (2009) The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits. Journal of Neuroscience 29(5): 1514–1524.

Costa‐Mattioli M, Gobert D, Stern E et al. (2007) eIF2alpha phosphorylation bidirectionally regulates the switch from short‐ to long‐term synaptic plasticity and memory. Cell 129(1): 195–206.

Edbauer D, Neilson JR, Foster KA et al. (2010) Regulation of synaptic structure and function by FMRP‐associated microRNAs miR‐125b and miR‐132. Neuron 65(3): 373–384.

Feinberg MP and Cochin J (1977) Studies on tolerance. II. The effect of timing on inhibition of tolerance to morphine by cycloheximide. Journal of Pharmacology and Experimental Therapeutics 203(2): 332–339.

Frey U, Krug M, Reymann KG and Matthies H (1988) Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Research 452(1–2): 57–65.

Hattori D, Chen Y, Matthews BJ, et al. (2009) Robust discrimination between self and non‐self neurites requires thousands of Dscam1 isoforms. Nature 461(7264): 644–648.

Hengst U, Deglincerti A, Kim HJ, Jeon NL and Jaffrey SR. (2009) Axonal elongation triggered by stimulus‐induced local translation of a polarity complex protein. Nature Cell Biology 11(8): 1024–1030.

Huang H, Tan BZ and Shen Y (2012) RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca(2)‐dependent inactivation. Neuron 73(2): 304–316.

Huber KM, Kayser MS and Bear MF (2000) Role for rapid dendritic protein synthesis in hippocampal mGluR‐dependent long‐term depression. Science 288(5469): 1254–1257.

Inda MC, Muravieva EV and Alberin CM (2011) Memory retrieval and the passage of time: from reconsolidation and strengthening to extinction. Journal of Neuroscience 31(5): 1635–1643.

Jung H, O'Hare CM and Holt CE. (2011) Translational regulation in growth cones. Current Opinion in Genetics and Development 21(4): 458–464.

Kasahara J, Fukunaga K and Miyamoto E. (2001) Activation of calcium/calmodulin‐dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. Journal of Biological Chemistry 276(26): 24044–24050.

Kelleher RJ 3rd and Bear MF (2008) The autistic neuron: troubled translation? Cell 135(3): 401–406.

Kelleher RJ 3rd, Govindarajan A, Jung HY, Kang H and Tonegawa S (2004) Translational control by MAPK signaling in long‐term synaptic plasticity and memory. Cell 116(3): 467–479.

Krichevsky AM and Kosik KS (2001) Neuronal RNA granules: a link between RNA localization and stimulation‐dependent translation. Neuron 32(4): 683–696.

Lee JA, Xing Y, Nguyen D et al. (2007) Depolarization and CaM kinase IV modulate NMDA receptor splicing through two essential RNA elements. PLoS Biology 5(2): e40.

Lin Q, Wei W and Coelho CM (2011) The brain‐specific microRNA miR‐128b regulates the formation of fear‐extinction memory. Nature Neuroscience 14(9): 1115–1117.

Liu‐Yesucevitz L, Bassell GJ, Gitler AD et al. (2011) Local RNA translation at the synapse and in disease. Journal of Neuroscience 31(45): 16086–16093.

Lodish H, Berk A, Matsudaira P et al. (2004) Molecular Cell Biology. New York, NY: WH Freeman and Company.

Maffei L and Berardi N (2002) Protein synthesis in the visual cortex is needed for ocular dominance plasticity. Neuron 34(3): 328–331.

Manahan‐Vaughan D, Kulla A and Frey JU (2000) Requirement of translation but not transcription for the maintenance of long‐term depression in the CA1 region of freely moving rats. Journal of Neuroscience 20(22): 8572–8576.

Martin KC, Casadio A, Zhu H et al. (1997) Synapse‐specific, long‐term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91(7): 927–938.

Michalon A, Sidorov M, Ballard TM et al. (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74(1): 49–56.

Miller S, Yasuda M, Coats JK et al. (2002) Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36(3): 507–519.

Muddashetty RS, Kelic S, Gross C, Xu M and Bassell GJ (2007) Dysregulated metabotropic glutamate receptor‐dependent translation of AMPA receptor and postsynaptic density‐95 mRNAs at synapses in a mouse model of fragile X syndrome. Journal of Neuroscience 27(20): 5338–5348.

Muslimov IA, Patel MV, Rose A and Tiedge H (2006) Spatial code recognition in neuronal RNA targeting: role of RNA–hnRNP A2 interactions. Journal of Cell Biology 194(3): 441–457.

Napoli I, Mercaldo V, Boyl PP et al. (2008) The fragile X syndrome protein represses activity‐dependent translation through CYFIP1, a new 4E‐BP. Cell 134(6): 1042–1054.

Oppenheim RW, Prevette D, Tytell M and Homma S (1990) Naturally occurring and induced neuronal death in the chick embryo in vivo requires protein and RNA synthesis: evidence for the role of cell death genes. Developmental Biology 138(1): 104–113.

Ostroff LE, Fiala JC, Allwardt B and Harris KM (2002) Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35(3): 535–545.

Pinkstaff JK, Chappell SA, Mauro VP, Edelman GM and Krushel LA (2001) Internal initiation of translation of five dendritically localized neuronal mRNAs. Proceedings of the National Academy of Sciences of the USA 98(5): 2770–2775.

Redondo RL and Morris RG (2011) Making memories last: the synaptic tagging and capture hypothesis. Nature Reviews Neuroscience 12(1): 17–30.

Sawtell NB, Philpot BD and Bear MF (2001) Activity‐dependent plasticity of glutamatergic synaptic transmission in the cerebral cortex. In: Kass J (ed.) The Mutable Brain: Dynamic and Plasitic Features of the Developing and Mature Brain, pp. 49–91. Amsterdam: Harwood Academic Publishers.

Schratt GM, Tuebing F, Nigh EA et al. (2006) A brain‐specific microRNA regulates dendritic spine development. Nature 439(7074): 283–289.

Solomon S (1999) POMC‐derived peptides and their biological action. Annals of the New York Academy of Sciences 885: 22–40.

Steward O and Worley PF (2001) A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites. Proceedings of the National Academy of Sciences of the USA 98(13): 7062–7068.

Swanger SA and Bassell GJ (2011) Making and breaking synapses through local mRNA regulation. Current Opinion in Genetics & Development 21(4): 414–421.

Tiruchinapalli DM, Oleynikov Y, Kelic S et al. (2003) Activity‐dependent trafficking and dynamic localization of zipcode binding protein 1 and beta‐actin mRNA in dendrites and spines of hippocampal neurons. Journal of Neuroscience 23(8): 3251–3261.

Ule J, Jensen KB, Ruggiu M et al. (2003) CLIP identifies Nova‐regulated RNA networks in the brain. Science 302(5648): 1212–1215.

Wang DO, Kim SM, Zhao Y et al. (2009) Synapse‐ and stimulus‐specific local translation during long‐term neuronal plasticity. Science 324(5934): 1536–1540.

Yao J, Sasaki Y, Wen Z, Bassell GJ and Zheng JQ (2006) An essential role for beta‐actin mRNA localization and translation in Ca2+‐dependent growth cone guidance. Nature Neuroscience 9(10): 1265–1273.

Zearfoss NR, Alarcon JM, Trifilieff P, Kandel E and Richter JD (2008) A molecular circuit composed of CPEB‐1 and c‐Jun controls growth hormone‐mediated synaptic plasticity in the mouse hippocampus. Journal of Neuroscience 28(34): 8502–8509.

Further Reading

Akins MR, Berk‐Rauch HE and Fallon JR (2009) Presynaptic translation: stepping out of the postsynaptic shadow. Frontiers in Neural Circuits 3: 17.

Alberts B, Johnson A, Lewis J et al. (2002) Molecular Biology of the Cell. New York, NY: Garland Science.

Cowan WM, Südhof TC and Stevens CF (2001) Synapses, pp. 1–767. Baltimore, MD: Johns Hopkins University Press.

Gold PE and Greenough WT (2001) Memory Consolidation: Essays in Honor of James L McGaugh. Washington, DC: American Psychological Association.

Kandel ER, Schwartz JH and Jessell TM (2000) Principles of Neural Science. New York, NY: McGraw‐Hill.

Osterweil EK, Krueger DD, Reinhold K and Bear MF (2010) Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. Journal of Neuroscience 30(46): 15616–15627.

Sonenberg N, Hershey JWB and Mathews MB (2001) Translational Control of Gene Expression. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.

Squire L, Bloom F, McConnell S et al. (2003) Fundamental Neuroscience. San Diego, CA: Academic Press.

Steward O and Schuman EM (2001) Protein synthesis at synaptic sites on dendrites. Annual Review of Neuroscience 24: 299–325.

Wells DG, Richter JD and Fallon JR (2000) Molecular mechanisms for activity‐regulated protein synthesis in the synapto‐dendritic compartment. Current Opinion in Neurobiology 10: 132–137.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Fallon, Justin R, and Taylor, Aaron B(May 2013) Protein Synthesis in Neurons. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000050.pub2]