Translational control by eIF2α kinases in long-lasting synaptic plasticity and long-term memory
Introduction
One of the more remarkable features of the brain is the ability to acquire and store new information as lasting memory traces. This continuous capacity to learn and remember allows one to process changes in the environment, retain new information, and adapt to behavioral choices over time. A fundamental question remains that intrigues modern neuroscientists: how are memories formed and stored at the cellular and molecular level? Behavioral studies performed in mice treated with the protein synthesis inhibitor puromycin provided the first molecular clue that protein synthesis is required for long-term memory (LTM) formation, but not for task acquisition and short-term memory (STM) formation (Flexner, Flexner, & Stellar, 1963). Since then, a plethora of pharmacological and genetic studies have highlighted the critical role for de novo gene expression and protein synthesis in LTM formation (Kandel, 2001, McGaugh, 2000).
Neurons can alter their molecular and physiological characteristics in response to temporal- and activity-dependent changes in their environment. Synaptic plasticity refers to the ability of the brain to change the efficacy (strengthening or weakening) of synaptic connections between neurons and is hypothesized as the cellular basis for learning and memory (Bliss and Collingridge, 1993, Malenka and Nicoll, 1999). These persistent, activity-dependent, changes in synaptic strength are triggered by de novo protein synthesis (Klann & Sweatt, 2008). Evidence indicating a role for protein synthesis at local synaptic sites stem from observations that neuronal dendrites and their spines contain polyribosomes (Steward & Levy, 1982), translation factors (Tang & Schuman, 2002), and mRNA (Crino & Eberwine, 1996) that can be translated into proteins to support synaptic activity. Consistent with this notion, local protein synthesis was shown to be necessary for long-lasting increases in synaptic strength induced by brain-derived neurotrophic factor (BDNF; Kang & Schuman, 1996). Similarly, rapid, local protein synthesis also was required for long-lasting decreases in synaptic strength induced by activation of group I metabotropic glutamate receptors (mGluR; Huber, Kayser, & Bear, 2000). Together, these findings indicate that protein synthesis can be triggered locally at activated synapses and is required for persistent, activity-dependent forms of synaptic plasticity, which in turn is thought to be essential for memory formation.
Although the initial report from Flexner et al. (1963) and other early studies identified new protein synthesis as a molecular requirement for memory formation, they offered little in the way of molecular translational control mechanisms because they relied mostly on the administration of general translation inhibitors into animals. In the last 10 years, however, a vast amount of genetic, biochemical, pharmacological, and physiological studies have increased our knowledge of the precise translational control mechanisms underlying long-lasting synaptic plasticity, memory formation, and cognitive function (Costa-Mattioli et al., 2009, Kelleher et al., 2004, Richter and Klann, 2009). In this review, we specifically discuss the functional role of eIF2α kinases and their regulation of activity-dependent synaptic plasticity and cognitive function, including learning and memory.
Section snippets
Translational control by eIF2α phosphorylation
Translational control can be defined as a change in either the efficiency or rate of mRNA translation. The process of mRNA translation can be divided into three main steps: initiation, elongation, and termination. Although regulation can occur at each step, translational control primarily occurs at the rate-limiting initiation step when the small 40S ribosomal subunit is recruited to the mRNA and positioned at the initiation codon (Jackson, Hellen, & Pestova, 2010). Translation initiation
eIF2α kinases
eIF2α phosphorylation is regulated by four serine/threonine (Ser/Thr) protein kinases, each of which phosphorylate eIF2α on Ser51. The four eIF2α kinases are heme-regulated inhibitor (HRI), the double-stranded (ds) RNA activated protein kinase (PKR), the general control non-derepressible-2 (GCN2), and the PKR-like endoplasmic reticulum (ER) resident protein kinase (PERK). These four eIF2α kinases share a conserved kinase domain, but respond differentially to various cellular stressors due to
GCN2 controls L-LTP and LTM
As previously mentioned, distinct eIF2α kinases phosphorylate eIF2α to control two fundamental processes that are crucial for the consolidation of long-term memories: de novo protein synthesis and CREB-mediated gene expression via the memory repressing factor ATF4. Evidence that regulation of eIF2α phosphorylation plays an important role in long-lasting synaptic plasticity and LTM was first provided by the observation that GCN2-deficient mice exhibit a lowered threshold for the induction of
PKR controls gene-specific translation, L-LTP, and LTM
Using a novel pharmacogenetic mouse model, Jiang et al. (2010) demonstrated that a selective increase in PKR-mediated eIF2α phosphorylation in CA1 hippocampal neurons impairs L-LTP and LTM. Accordingly, the increase in eIF2α phosphorylation was associated with an increase in ATF4 translation and the suppression of CREB-dependent gene expression (Jiang et al., 2010), including that of BDNF, a key protein involved in L-LTP and the consolidation of LTM (Bekinschtein et al., 2008). It should be
PERK controls ATF4 translation and behavioral flexibility
Using mouse behavioral genetics and biochemistry, it was demonstrated that PERK plays a crucial role in regulating behavioral flexibility (Trinh et al., 2012). Previous studies showed that global inactivation of PERK results in severe developmental abnormalities (Wei et al., 2008, Zhang et al., 2002). To rule out the possibility that the effects of PERK on synaptic and cognitive function occur during development, mice were generated in which PERK was selectively removed in the forebrain at
Conclusions and future directions
It is now evident that eIF2α kinases and their ability to impact translational control via the phosphorylation of eIF2α are critical for long-lasting plasticity of synaptic connections and for cognitive functions that rely on such plasticity in the brain. One intriguing insight from the studies of the role of eIF2α kinases in synaptic plasticity thus far is that eIF2α phosphorylation is divergently regulated during LTP and LTD. Moreover, these studies suggest that eIF2α kinases, such as PERK
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