Chapter 5 Translational control of gene expression: A molecular switch for memory storage
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)
- et al.
Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J. Biol. Chem.
(2004) - et al.
Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture
Cell
(2002) - et al.
Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change
Cell
(1995) - et al.
Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins
Neuron
(2003) - et al.
eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory
Cell
(2007) - et al.
Activation of GCN2 in UV-irradiated cells inhibits translation
Curr. Biol.
(2002) Gene-specific regulation by general translation factors
Cell
(2002)- et al.
Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F
J. Biol. Chem.
(1987) - et al.
Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala
Neuron
(1999) Neuronal mechanism in the responses to amino acid deficiency
J. Nutr.
(1993)
Phosphorylation of eIF2alpha is involved in the signaling of indispensable amino acid deficiency in the anterior periform cortex of the brain rats
J. Nutr.
Regulated translation initiation controls stress-induced gene expression in mammalian cells
Mol. Cell
eIF3: a versatile scaffold for translation initiation complexes
Trends Biochem. Sci.
Translational regulatory mechanisms in persistent forms of synaptic plasticity
Neuron
Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats
Brain. Res. Bull.
Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin
Cell
Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage
Cell
The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab.
Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression
J. Biol. Chem.
Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon
Cell
Tagging the Hebb synapse: reply
Trends Neurosci.
Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions
J. Biol. Chem.
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.
Compartmentalized synthesis and degradation of proteins in neurons
Neuron
Dendritic protein synthesis, synaptic plasticity, and memory
Cell
Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin
J. Biol. Chem.
CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila
Cell
Memory suppressor genes: inhibitory constraints on the storage of long-term memory
Science
Puromycin effect on memory fixation in the goldfish
Science
Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase
Eur. J. Biochem.
A synaptic model of memory: long-term potentiation in the hippocampus
Nature
Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA
Learn. Mem.
A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress
Science
Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica
Science
Inhibitor of protein synthesis blocks long-term behavioral sensitization in the isolated gill-withdrawal reflex of Aplysia
J. Neurobiol.
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.
Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2
EMBO J.
Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2
Nature
Cited by (53)
Proteostasis and resilience: on the interphase between individual's and intracellular stress
2022, Trends in Endocrinology and MetabolismEmerging roles of the unfolded protein response (UPR) in the nervous system: A link with adaptive behavior to environmental stress?
2020, International Review of Cell and Molecular BiologyPERK as a hub of multiple pathogenic pathways leading to memory deficits and neurodegeneration in Alzheimer's disease
2018, Brain Research BulletinCitation Excerpt :One of such molecules that undergo the gene-specific translational upregulation upon eIF2α phosphorylation is activating transcription factor 4 (ATF4) (Harding et al., 2000; Vattem and Wek, 2004), which is a repressor of cAMP response element binding protein (CREB)-dependent transcription critical for memory consolidation (also called CREB-2) (Abel et al., 1998; Chen et al., 2003; Silva et al., 1998). The molecular machinery of eukaryotic translation initiation and its regulation have been described in detail in previous reviews (Costa-Mattioli and Sonenberg, 2008; Costa-Mattioli et al., 2009; Donnelly et al., 2013; Jackson et al., 2010). Synaptic plasticity can occur through strengthening and weakening of pre-existing synapses − i.e., long-term potentiation (LTP) and long-term depression (LTD), respectively (Bliss and Collingridge, 1993; Malenka and Bear, 2004), while it may also involve remodeling of synaptic architecture to alter synaptic connectivity − i.e., structural synaptic plasticity (Holtmaat and Svoboda, 2009).
mRNA Trafficking to Synapses and Memory Formation
2017, Learning and Memory: A Comprehensive ReferenceBehavioral tagging: A novel model for studying long-term memory
2016, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Acquisition of new information is stored in the form of two temporally and mechanistically different memory types: a short term memory (STM) and a long term memory (LTM). To establish the process of LTM, newly synthesized proteins are must so as to stabilize synaptic changes (Costa-Mattioli and Sonenberg, 2008). The current models of synaptic plasticity suggest that stable changes in synaptic weight modify the activity of specific neuronal circuits (Martin et al., 2000).