Chapter 5 Translational control of gene expression: A molecular switch for memory storage

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Abstract

A critical requirement for the conversion of the labile short-term memory (STM) into the consolidated long-term memory (LTM) is new gene expression (new mRNAs and protein synthesis). The first clues to the molecular mechanisms of the switch from short-term to LTM emerged from studies on protein synthesis in different species. Initially, it was shown that LTM can be distinguished from STM by its susceptibility to protein synthesis inhibitors. Later, it was found that long-lasting synaptic changes, which are believed to be a key cellular mechanism by which information is stored, are also dependent on new protein synthesis. Although the role of protein synthesis in memory was reported more than 40 years ago, recent molecular, genetic, and biochemical studies have provided fresh insights into the molecular mechanisms underlying these processes. In this chapter, we provide an overview of the role of translational control by the eIF2α signaling pathway in long-term synaptic plasticity and memory consolidation.

Section snippets

Overview of translation initiation in eukaryotes

Translational control is an important mechanism by which cells govern gene expression, providing a rapid response by the cell without invoking nuclear pathways for mRNA synthesis and transport. In systems with little or no transcriptional control (e.g., reticulocytes, sea urchin eggs, Drosophila early embryogenesis, and oocytes), translation is the major mode of regulation of gene expression (Mathews et al., 2007a). Initiation is the rate-limiting step of translation and the main target of

Short-term and long-term memory

The idea about two memory systems (STM and LTM) has emerged from the study of patients with memory impairments. A classic in the medical literature is the case of a patient, H.M., who suffered from seizures due to a head injury in a bicycle accident when he was 9 years-old (Scoville and Milner, 1957). To relieve his intractable seizures, neurosurgeons performed a bilateral surgical excision of the medial temporal region. As a result of the surgery H.M. exhibited a severe impairment in LTM but

Identification of GCN2 as regulator of learning and memory and characterization of GCN2 knockout mice

Though we knew that memory consolidation requires new protein synthesis, the molecular mechanisms by which translation controls these processes remained obscure. GCN2 has several interesting features: GCN2-mediated phosphorylation of eIF2α suppresses general translation and selectively stimulates the translation of ATF4 (Dever et al., 2007; Pestova et al., 2007; Ron and Harding, 2007). Interestingly, ATF4 and its homologs are repressors of long-lasting synaptic plasticity and memory formation

GCN2 in the brain regulates selection of balanced diet

Omnivorous animals such as rats reject diets lacking essential amino acids. Selection of such a balanced diet plays an important role in human evolution. It has been reported that neurons of the apical periform cortex, which project to appropriate feeding neuronal circuits, are activated by intracellular indispensable amino acids (Haberly and Price, 1978). The apical periform cortex appears to be critical for such an adversive response, because bilateral lesion of this region abolishes the bias

A master switch for the conversion from short-term to long-term synaptic plasticity and memory formation

Consolidation of long-term memories requires the expression of new genes (Squire, 1987). Thus, if` new gene expression is the rate-limiting step necessary to strengthen existing synaptic connections between neurons, how is this process turned on? If one could find such a mechanism and switch it on, then stimulation that normally elicits only E-LTP and STM should lead to L-LTP and LTM. This was the goal of our research. In diverse phyla, a key component in memory formation is the transcription

Summary

Significant advances in studies of translational control of synaptic plasticity and memory formation have emerged in the last few years. GCN2-mediated phosphorylation of eIF2α and signaling downstream is an ancient signaling pathway, which is critical for the regulation of various biological processes. Recent well-integrated multidisciplinary approaches (molecular biology, genetics, electrophysiology, and behavior) have revealed the crucial role of eIF2α phosphorylation in synaptic plasticity

Acknowledgments

We thank Kresimir Krnjevic for comments on the manuscript. This work was supported by a Team Grant from the Canadian Institute of Health Research (CIHR) to M.C.-M and N.S. and a Howard Hughes Medical Institute (HHMI) grant to N.S.

References (76)

  • D.W. Gietzen et al.

    Phosphorylation of eIF2alpha is involved in the signaling of indispensable amino acid deficiency in the anterior periform cortex of the brain rats

    J. Nutr.

    (2004)
  • H.P. Harding et al.

    Regulated translation initiation controls stress-induced gene expression in mammalian cells

    Mol. Cell

    (2000)
  • A.G. Hinnebusch

    eIF3: a versatile scaffold for translation initiation complexes

    Trends Biochem. Sci.

    (2006)
  • R.J. Kelleher et al.

    Translational regulatory mechanisms in persistent forms of synaptic plasticity

    Neuron

    (2004)
  • M. Krug et al.

    Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats

    Brain. Res. Bull.

    (1984)
  • G. Malleret et al.

    Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin

    Cell

    (2001)
  • K.C. Martin et al.

    Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage

    Cell

    (1997)
  • A.-C. Maurin et al.

    The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab.

    (2005)
  • H. Mellor et al.

    Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression

    J. Biol. Chem.

    (1994)
  • E. Meurs et al.

    Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon

    Cell

    (1990)
  • R.G. Morris et al.

    Tagging the Hebb synapse: reply

    Trends Neurosci.

    (1999)
  • J. Narasimhan et al.

    Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions

    J. Biol. Chem.

    (2004)
  • J. Santoyo et al.

    Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2alpha (eIF-2alpha) kinase from Drosophila melanogaster. Homology to yeast GCN2 protein kinase

    J. Biol. Chem.

    (1997)
  • O. Steward et al.

    Compartmentalized synthesis and degradation of proteins in neurons

    Neuron

    (2003)
  • M.A. Sutton et al.

    Dendritic protein synthesis, synaptic plasticity, and memory

    Cell

    (2006)
  • N. Takei et al.

    Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin

    J. Biol. Chem.

    (2001)
  • J.C. Yin et al.

    CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila

    Cell

    (1995)
  • T. Abel et al.

    Memory suppressor genes: inhibitory constraints on the storage of long-term memory

    Science

    (1998)
  • B.W. Agranoff et al.

    Puromycin effect on memory fixation in the goldfish

    Science

    (1964)
  • J.J. Berlanga et al.

    Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase

    Eur. J. Biochem.

    (1999)
  • T.V. Bliss et al.

    A synaptic model of memory: long-term potentiation in the hippocampus

    Nature

    (1993)
  • R. Bourtchouladze et al.

    Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA

    Learn. Mem.

    (1998)
  • M. Boyce et al.

    A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress

    Science

    (2005)
  • T.J. Carew et al.

    Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica

    Science

    (1983)
  • V.F. Castellucci et al.

    Inhibitor of protein synthesis blocks long-term behavioral sensitization in the isolated gill-withdrawal reflex of Aplysia

    J. Neurobiol.

    (1989)
  • J.J. Chen et al.

    Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • K.L. Chong et al.

    Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2

    EMBO J.

    (1992)
  • M. Costa-Mattioli et al.

    Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2

    Nature

    (2005)
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