Translational Control Through the eIF4E Binding Proteins in the Brain
Abstract and Keywords
Translation of messenger RNA (mRNA) into protein (protein synthesis) is a highly regulated process that controls gene expression. Various signaling pathways, including the mammalian target of rapamycin (mTOR), control mRNA translation at the initiation step. mTOR is part of a multi-subunit complex that regulates mRNA translation initiation by phosphorylating and inactivating the eukaryotic initiation factor 4E binding proteins (4E-BPs). 4E-BPs are a central mechanism in the control of cap-dependent translation in the brain. This chapter reviews the involvement of the 4E-BPs, particularly 4E-BP2, in brain development and synaptic transmission. Furthermore, it discusses the involvement of 4E-BP2 in autistic-like alterations, learning and memory, circadian rhythm regulation, and its roles in the pathophysiology and treatment of psychiatric (depressive disorders, schizophrenia) and neurodegenerative disorders (Parkinson’s).
Eukaryotic Translation Initiation Factor 4E Binding Proteins: Basic Biochemical Considerations
Eukaryotic translation initiation factor 4E (eIF4E) is central to mRNA translation initiation as a component of the eIF4F translation initiation complex, along with eIF4G and eIF4A. eIF4E recognizes the 5′-cap structure, enabling the recruitment of the small ribosomal subunit to mRNA through eIF4G and eIF3 (Sonenberg, Morgan, Merrick, & Shatkin, 1978).
eIF4E cap-binding cavity specifically interacts with the m7G(5′)ppp(5′)N (where N is typically G or A) cap of an mRNA (reviewed in (Rhoads, 2009; Topisirovic, Svitkin, Sonenberg, & Shatkin, 2011). eIF4E also interacts with eIF4G, on the convex side of the cap-binding cavity, by binding to a YX4Lϕ motif on eIF4G (where ϕ denotes hydrophobic residue, usually leucine, methionine, or phenylalanine). The interaction of eIF4E with the mRNA 5′-cap structure is dramatically enhanced by eIF4G (Haghighat, Mader, Pause, & Sonenberg, 1995; Ptushkina et al., 1998).
A bona fide mechanism for activity regulation of eIF4E is through its interaction with the eIF4E-binding proteins (4E-BPs). 4E-BPs are small, acidic, heat-stable proteins first described in vertebrates as a three-member protein family—4E-BP1, 4E-BP2 and 4E-BP3—which share a 55% amino acid sequence identity.
The 4E-BPs bind eIF4E and prevent its interaction with eIF4G. 4E-BPs use the same YX4Lϕ sequence to competitively bind eIF4E (Hershey et al., 1999; Marcotrigiano, Gingras, Sonenberg, & Burley, 1999), preventing eIF4E-eIF4G interaction and inhibiting cap-dependent translation by blocking the assembly of the eIF4F complex (Martineau, Azar, Bousquet, & Pyronnet, 2013; Rhoads, 2009; Richter & Sonenberg, 2005). Deletion of this sequence in the 4E-BPs or mutation of either the tyrosine or the leucine to alanine abrogates their eIF4E binding (Mader, Lee, Pause, & Sonenberg, 1995; Poulin, Gingras, Olsen, Chevalier, & Sonenberg, 1998).
The association of 4E-BPs with eIF4E is reversible and regulated by phosphorylation. Mammalian 4E-BPs are targets of mTOR (mammalian/mechanistic target of rapamycin) kinase, a key sensor of nutrient status. Increase phosphorylation of 4E-BPs promotes dissociation of eIF4E and thus increases translation activity (Gingras et al., 1999).
The 4E-BPs contain three functional domains: the eIF4E-binding domain (Mader et al., 1995), a C-terminal TOR (target of rapamycin) signaling motif (TOS; Schalm & Blenis, 2002), and an N-terminal RAIP (Arg13, Ala14, Ile15, Pro16) motif (Tee & Proud, 2002). The TOS and RAIP motifs contribute to the binding of Raptor (Eguchi et al., 2006; Lee, Healy, Fonseca, Hayashi, & Proud, 2008), a scaffold protein of mTOR complex 1 (mTORC1) that bridges mTOR and the 4E-BPs and is necessary for efficient phosphorylation of the 4E-BPs (Hara et al., 2002; Schalm, Fingar, Sabatini, & Blenis, 2003).
Phosphorylated 4E-BPs have been generally accepted as a marker of activated mTORC1 signaling. Seven phosphorylation sites have been identified in 4E-BP1: Tyr 37, Thr 46, Ser 65, Thr 70, Ser 83, Ser 101, and Ser 112 (numbering based on human 4E-BP1; Martineau et al., 2013). The first five phosphorylation sites are phylogenetically conserved among eukaryotes; mTORC1-dependent phosphorylation of 4E-BP1 proceeds in a hierarchical way: initial phosphorylation of Thr 37 and Thr 46 is followed by Thr 70 and Ser 65 (Gingras et al., 1999; Gingras, Raught, & Sonenberg, 2001). Phosphorylation at Ser 101 is required for efficient phosphorylation at Ser 65 (Wang, Li, Parra, Beugnet, & Proud, 2003), while phosphorylation at Ser 112, directly affects binding of 4E-BP1 to eIF4E, without influencing phosphorylation of other sites (Wang et al., 2003). 4E-BP2 and 4E-BP3 lack residues corresponding to both Ser 101 and Ser 112 (Wang et al., 2003).
Recently, several other kinases have been shown to phosphorylate 4E-BP1 (Qin, Jiang, & Zhang, 2016). For example, GSK3β phosphorylates 4E-BP1 at Thr 37 and Thr 46 in some cancer cells (Shin et al., 2014); P38-dependet phosphorylation of 4E-BP1 has also been shown in vitro in response to UV irradiation (G. Liu, Zhang, Bode, Ma, & Dong, 2002); cyclin-dependent kinase, cdc2/CDK1, can phosphorylate 4EBP1 at Thr 70 in HeLa cells (Heesom, Gampel, Mellor, & Denton, 2001) and in a breast cancer cell line (Greenberg & Zimmer, 2005). Finally, LRRK2 (leucine-rich repeat kinase 2) is one of the physiological kinases for 4E-BP at the Thr 37/46 sites, and it is the only one, other than mTOR, that that has been shown to phosphorylate 4E-BP in the nervous system of Drosophila (Imai et al., 2008). It is yet to be determined whether any of these kinases contributed to the regulation of the 4E-BPs in the mammalian brain.
Structural studies in solution using nuclear magnetic resonance show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of the three mammalian proteins (Bah et al., 2015). Bah and coworkers demonstrated that phosphorylation of Thr 37 and Thr 46 induces folding of residues Pro 18-Arg 62 of 4E-BP2 into a four-stranded β-domain that sequesters the helical YX4LΦ motif inside a partially buried β-strand, blocking its accessibility to eIF4E (Bah et al., 2015). The structurally rigid state of phosphorylated Thr 37-Thr 46 of 4E-BP2 presented a decreased affinity for eIF4E by a factor of approximately 4000 (Bah et al., 2015).
Distribution of 4E-BPs in the Brain
Although there is no comprehensive mapping of the 4E-BPs in the mammalian brain, initial studies investigating the distribution of the 4E-BPs across different tissues found that 4E-BP2 is the most abundant isoform in the brain, while low but detectable levels of 4E-BP1 were also detected (Banko et al., 2005; Tsukiyama-Kohara et al., 2001). In contrast, there are no detectable levels of 4E-BP3 in the brain at baseline conditions (Banko et al., 2005; Tsukiyama-Kohara et al., 2001).
In contrast to the widespread distribution of 4E-BP2 (Banko et al., 2005), 4E-BP1 appears to exhibit a restricted expression pattern in the brain, with higher levels in the suprachiasmatic nucleus, while sparse 4E-BP1 immunoreactivity is also detected in the hippocampus and cortex (Cao et al., 2013).
Deamidation of 4E-BP2 in the Adult Mouse Brain
4E-BP2 is widely expressed in the adult mouse brain (Banko et al., 2005; Tsukiyama-Kohara et al., 2001); however, its phosphorylation is not readily detectable in the adult CNS in unstimulated conditions (Bidinosti, Ran, et al., 2010). Although the reason for the lack of 4E-BP2 phosphorylation in CNS is still unclear, research on this topic led to the discovery of an additional posttranslational modification for 4E-BP2.
4E-BP2 undergoes a pH-dependent non-enzymatic deamidation in the adult mouse brain, which results in greater affinity for raptor and lower affinity for eIF4E (Bidinosti, Ran, et al., 2010). The deamidation can occur in two arginine residues (N99 and N102) that are not conserved in the murine or human 4E-BP1, therefore it is hypothesized that only 4E-BP2 undergoes this modification (Bidinosti, Ran, et al., 2010). Importantly, 4E-BP2 deamidation correlates with an age-dependent decrease in activation, at baseline, of the PI3K-Akt-mTOR signaling pathway in whole brain extracts (Bidinosti, Ran, et al., 2010). This decrease in upstream signaling did not correlate with a decrease in eIF4F complex; given the lower affinity of deamidated 4E-BP2 for eIF4E in adult brain, it was proposed that the progressive increases in 4E-BP2 deamidation contributed to keeping a steady level of eIF4F throughout development (Bidinosti, Ran, et al., 2010). Once deamidated, 4E-BP2 becomes a substrate for protein L-isoaspartyl methyltransferase (PIMT)-mediated repair of isoaspartyl residues (Bidinosti, Martineau, Frank, & Sonenberg, 2010).
Genes Regulated by 4E-BP1 and 4E-BP2 in the Brain
A landmark study in mouse embryonic fibroblasts (MEFs) used ribosome profiling (Ingolia, Ghaemmaghami, Newman, & Weissman, 2009) to determine which mRNAs were sensitive to mTOR inhibition (Thoreen et al., 2012). This analysis determined that the most sensitive mRNAs to the mTOR inhibitor Torin-1 were TOP or TOP-like mRNAs, which are defined by a cytidine immediately after the 5′ cap, followed by an uninterrupted stretch of 4–14 pyrimidines (Jefferies, Reinhard, Kozma, & Thomas, 1994; Meyuhas, 2000), and tend to encode proteins associated with translation (Iadevaia, Caldarola, Tino, Amaldi, & Loreni, 2008; Meyuhas, 2000). Most of the Torin-1 sensitive mRNAs were regulated through the 4E-BPs (Thoreen et al., 2012). Furthermore, contrary to the hypothesis that RNAs with long and complex 5′ untranslated regions (UTRs) are regulated through a 4E-BP-dependent mechanism (Hay & Sonenberg, 2004), this study found no evidence that 5′ UTR length or complexity correlated positively with sensitivity to mTOR inhibition (Thoreen et al., 2012).
In the brain, there is experimental evidence that mTORC1 signaling is necessary for the translation of several mRNAs that are not involved in the protein synthesis process, that is, Ca2+/calmodulin-dependent kinase II alpha (CamKIIa), AMPA receptor subunits, microtubule-associated protein (MAP2), postsynaptic density protein 95 (PSD-95), and glutamate receptor interaction protein (Hou & Klann, 2004; Mameli, Balland, Lujan, & Luscher, 2007; Schratt, Nigh, Chen, Hu, & Greenberg, 2004; Slipczuk et al., 2009). Presumably, the 4E-BPs contribute to the translational regulation of a number of these and other genes, but an exhaustive unbiased approach has yet to be applied to identify the targets of their regulation.
Intriguingly, absence in Eif4ebp2 did not result in changes in total protein synthesis in the adult brain (Gkogkas et al., 2013), although several mRNA targets for 4EBP1 and 4E-BP2 have been already confirmed/identified. For example, Gria1 and Gria2 mRNAs, encoding for the GluA1 and GluA2 AMPA receptor subunits (Ran et al., 2013), were identified as sensitive to 4E-BP2 and contributing to the synaptic effects observed in Eif4ebp2 KO mice (Ran et al., 2013). In the study of autism-related genes, it was demonstrated that translation of neuroligins 1, 2, and 3 is increased in the hippocampi of Eif4ebp2 KO and Eif4e transgenic mice (Gkogkas et al., 2013). It is unclear whether 4E-BP1 also contributes to the translational regulation of these genes in the brain; however, at least one mRNA has been shown to be regulated by 4E-BP1 in the brain: the Vip mRNA, encoding the vasoactive intestinal peptide (VIP; Cao et al., 2013).
The presence of several secondary structures in the 5′ UTR in the neuroligin genes was proposed to be involved in the sensitivity to 4E-BP2 (Gkogkas et al., 2013). The latter suggests that some structural elements in the 5′UTR of the mRNAs can contribute to the sensitivity toward the 4E-BPs (Gkogkas et al., 2013). The reason behind the apparent discrepancy between these findings and those in MEFs is unclear. One potential explanation is the contrast between acute effects of mTOR inhibition (as those studied in MEFs; Thoreen et al., 2012) and the long-term adaptations that occur with the chronic absence of the 4E-BPs as studied in the Eif4ebp1 –/– and Eif4ebp2 –/– mice. In addition, there is evidence that in adult mice, the genes related to the translational machinery itself are translationally suppressed in the hippocampus (Cho et al., 2015) through an unknown mechanism, adding another layer of complexity in the understanding of the translational control in the brain.
4E-BP2 in Brain Development and Neurodevelopmental Disorders
Overactive mTORC1 signaling is a signature of many disorders with cortical malformations, ranging from tuberous sclerosis complex with focal dysplasias to hemimegalencephaly with more diffuse, hemispheric aberrations (Crino, 2011). Focal increased activity of mTORC1 in the anterior cingulate cortex (ACC) at E15.5 leads to increased neuronal soma size, increased complexity of dendritic arbors, and mislamination, whereby neurons with greater mTORC1 are ectopically retained in deeper cortical layers (i.e., neurons fail to migrate out toward the external layers 2/3 of ACC; Lin, Hsieh, Kimura, Malone, & Bordey, 2016). These effects, along with increased cap-dependent translation, are dependent on the 4E-BPs, since they can be normalized when a phosphorylation-resistant mutant form of 4E-BP1 is overexpressed. In support of this, knock-down of endogenous 4E-BP2, leading to enhanced cap-dependent translation, is sufficient to induce ectopic localization of neurons to deeper layers of the cortex, indicating that the 4E-BPs are central in regulating cortical lamination and neuronal morphology (Lin et al., 2016).
Intriguingly, markers of decreased autophagy and increased endoplasmic reticulum stress (both induced by increased mTORC1 in neuronal progenitors) appear normalized after overexpression of phosphorylation-resistant 4E-BP1 and induced by 4E-BP2 knock down (Lin et al., 2016). These results suggest the possibility that cap-dependent translational control may influence the autophagy and ER stress response, in addition to the direct effect of mTORC1 on these cellular functions. The extent to which translation-regulated changes to autophagy and ER stress signaling contributes, if at all, to mTORC1-induced mislamination is yet to be determined (Lin et al., 2016).
In addition, 4E-BP2 is important for mTORC1-mediated control of axon elongation in ACC neurons in vivo. In this regard, hyperactive mTORC1 at E15.5 in ACC neurons led to increased axonal growth projecting contralaterally into the corpus callosum and into the contralateral cortices (Gong et al., 2015). This effect was reversed by co-transfecting a constitutively active 4E-BP1 (Gong et al., 2015). Neither axonal branching, direction, or growth appeared altered by the manipulation of mTORC1 or the 4E-BPs (Gong et al., 2015). Intriguingly, 4E-BP1 phosphorylation stimulated β-actin translation in Xenopus laevis retinal growth cones, which controlled directional turning of the growth cone (Leung et al., 2006). It is unclear whether the involvement of 4E-BP1 in growth cone response to guidance cues also extends to the mammalian brain.
In early postnatal development, mTORC1 activity in the subventricular zone (SVZ) controls neural stem cell (NSC) self-renewal, and generation of transit amplifying cells (TACs) and, therefore, regulates the production of newborn neurons (Hartman et al., 2013). In this regard, decreased and increased mTORC1 function decreases and increases, respectively, generation of TACs at the expense of NSC self-renewal. In other words, mTORC1 activity does not induce NSCs to enter the cell cycle but, rather, is a regulator of their differentiation into their daughter cells: Mash1+ TACs in the neonatal SVZ. Importantly, this effect was mediated by 4E-BP2 and cap-dependent translation, and not S6K1/2, as constitutively active 4E-BP1 mimicked the effects of decreased mTORC1, while knock-down of 4E-BP2 mimicked those of overactive mTORC1 (Hartman et al., 2013).
Overall, during embryonic development the 4E-BP2 control cortical migration, it appears to contribute to autophagy and ER stress, dendritic arborization, and axonal growth. Furthermore, 4E-BP2 is an important regulator of postnatal neurogenesis, by controlling the differentiation of neuronal stem cells in the SVZ. These findings are central, given the overactivation of mTORC1 in several disorders with high rates of autism, including tuberous sclerosis (Tsai et al., 2014), PTEN, and fragile X syndrome (Sharma et al., 2010).
Role of 4E-BP2 in Autism and Synaptic Transmission
Supporting the importance of 4E-BPs and cap-dependent translation in autism spectrum disorders (ASD), absence of 4E-BP2 in Eif4ebp2 KO mice leads to decreased social interaction, decrease ultrasonic vocalizations, and increased repetitive behaviors (Gkogkas et al., 2013). The social deficits could be rescued by pharmacological inhibition of eIF4F. In this regard, while ASD is a neurodevelopmental disorder, countless studies have demonstrated adult reversal of behavioral and synaptic phenotypes in ASD mouse models (e.g., Aguilar-Valles et al., 2015; Gkogkas et al., 2013). In this regard, acute administration of group I metabotropic glutamate receptor antagonists rescued the social deficits and increased repetitive behaviors (Aguilar-Valles et al., 2015), suggesting that like Fmr1 KO mice, a model of fragile X syndrome, increased cap-dependent mRNA translation in the brain results in increased activity of mGluR1 and mGluR5, which can be targeted to normalize autism-like behaviors.
Intriguingly, no major structural alterations are evident in the brain of Eif4ebp2 KO mice (Banko et al., 2005), although studies in this mouse strain may have not been detailed enough to reveal them. Thus, the relationship between the proposed developmental roles of 4E-BP2 (Gong et al., 2015; Hartman et al., 2013; Lin et al., 2016; described in the previous section) and the behavioral deficits observed in the full body knockout mice (Aguilar-Valles et al., 2015; Banko, Hou, Poulin, Sonenberg, & Klann, 2006; Banko et al., 2005, 2007; Gkogkas et al., 2013) remain unexplored and deserve more attention.
In addition to the behavioral deficits, Eif4ebp2 KO mice present increased hippocampal synaptic activity, measured in CA1 pyramidal cells (Bidinosti, Martineau, et al., 2010; Gkogkas et al., 2013). CA1 miniature excitatory postsynaptic currents are increased in amplitude, frequency, and total charge (Bidinosti, Ran, et al., 2010; Gkogkas et al., 2013). In addition, miniature inhibitory postsynaptic currents are also increased in amplitude and total charge, but not in frequency, thus creating and excitatory/inhibitory (E/I) imbalance that is thought to contribute to the autistic-like behavioral deficits (Gkogkas et al., 2013). Importantly, overexpressed neuroligin 1, but not neuroligin 2, was involved in the induction of increased E/I ratio and decreased social interaction in the Eif4ebp2 KO mice (Gkogkas et al., 2013).
Intriguingly, attempted rescue of increased mEPSC in hippocampal neurons with constitutively deamidated 4E-BP2 results in normalized mEPSC frequency and amplitude; yet, some aspects of the mEPSC remained altered with deamidated 4E-BP2 transfection. Specifically, there was an increase in total charge of mESPC and a slower rise and decay kinetics compared to neurons expressing the wildtype non-deamidated 4E-BP2 (Bidinosti, Martineau, et al., 2010). These findings suggest that in postnatal development, 4E-BP2 deamidation contributes to an increase in mEPSC charge and slower kinetics in the hippocampus, although this remains to be directly demonstrated (Bidinosti, Martineau, et al., 2010).
The effects of 4E-BP2 in synaptic transmission appear to be region specific, as enhanced mTORC1 activity in the ACC leads to reduced EPSC frequency in pyramidal neurons, which can be rescued by overexpressing a constitutively active form of 4E-BP1 (Lin et al., 2016). In addition, enhanced mTORC1 in ACC pyramidal neurons results in increased the membrane resting potential, which was also dependent on 4E-BP control of translation.
4E-BPs in the Control of Circadian Rhythms
Circadian clocks have evolved to adaptively align internal biological processes to daily environmental changes (Lim & Allada, 2013). Circadian rhythms are self-sustaining, persisting even in the absence of external time cues. However, the period of these clocks only approximates 24 h. These self-sustaining clocks are reset by oscillating inputs such as light, temperature, or feeding to synchronize with the 24 h environment (Lim & Allada, 2013). The mechanism for intracellular generation of circadian rhythms is based in part on a transcription-translation feedback loop in which CLOCK and BMAL1 proteins induce the expression of the Period (Per1, Per2 and Per3) and Cryptochrome genes (Cry1 and Cry2), whose protein products interact and inhibit CLOCK/BMAL1 transcriptional activity (Lim & Allada, 2013).
mRNA translation is also a critical event for light-entrainment of the clock. Along these lines, work performed in a wide range of clock model systems has shown that the application of translation inhibitors suppresses light entrainment (Johnson & Nakashima, 1990; Murakami, Nishi, Katayama, & Nasu, 1995; Raju, Yeung, & Eskin, 1990; Zhang, Takahashi, & Turek, 1996). Furthermore, rhythmic activation of signaling pathways that regulate translation initiation, in particular the mTORC1 pathway, results in circadian time-dependent phosphorylation of translation factors in suprachiasmatic nucleus (SCN) clock neurons, as well as peripheral clock tissues (Cao, Anderson, Jung, Dziema, & Obrietan, 2011; Jouffe et al., 2013).
Regarding the specific involvement of the 4E-BPs in mammals, 4E-BP1 is enriched in the central clock pacemaker, the suprachiasmatic nucleus (SCN; Cao et al., 2013). In the SCN, 4E-BP1 phosphorylation varies with the circadian rhythm in mice kept in constant darkness (Cao et al., 2013), and this phosphorylation can be increased by light stimulation, downstream of mTORC1 activation (Cao, Lee, Cho, Saklayen, & Obrietan, 2008). One of the main phenotypes of the Eif4ebp1 KO mice is the accelerated re-entrainment of the circadian wheel-running behavior in “jet-lag” models, where there the light schedule is either delayed or advanced abruptly (Cao et al., 2013). This effect is reflected by concurrent changes in PER1 and PER2 levels, that recover faster in Eif4ebp1 KO compared to wildtype mice (Cao et al., 2013). Eif4ebp1 KO mice are also more resilient to the disruptive effects of constant light on circadian wheel-running compared to wildtype mice (Cao et al., 2013). These phenotypes indicate the importance of the mTORC1-4E-BP1 activation in light-induced resetting of the circadian clock. Furthermore, as 4E-BP1 controls the translation of the Vip mRNA (Cao et al., 2013), which is required for coordination of circadian rhythms both in the SCN and in behavior (Aton, Colwell, Harmar, Waschek, & Herzog, 2005), and its elevated translation in the brain of 4E-BP1 may be responsible for the observed circadian phenotypes.
Roles in Synaptic Plasticity and Memory Formation
Several studies have demonstrated activation and requirement of the mTORC1 for memory formation (Costa-Mattioli, Sossin, Klann, & Sonenberg, 2009; Hoeffer & Klann, 2010; Qi, Mizuno, Yonezawa, Nawa, & Takei, 2010), including phosphorylation of mTOR, and the mTORC1 substrates S6K1 and 4E-BP1/2 (Kelleher, Govindarajan, Jung, Kang, & Tonegawa, 2004; Saraf, Luo, Morris, & Storm, 2014; Tang et al., 2002). Furthermore, downstream of 4E-BP phosphorylation, there is a dose-dependent increase in eIF4F formation following LTP-inducing electrical and LTD-inducing chemical stimulation in the hippocampus (Banko et al., 2005). However, the role of mRNA translation in memory consolidation is much more nuanced, involving not only activating (such as mTORC1), but also translationally repressive pathways (Cho et al., 2015; Costa-Mattioli et al., 2005, 2007).
As 4E-BP2 appears to be more ubiquitously expressed 4E-BP in the brain (Tsukiyama-Kohara et al., 2001), these mutant mice have been further investigated for effects on memory formation, although it is possible that the more anatomically restricted, 4E-BP1, may also have a role in this process. Since mTORC1 is important for memory formation (Stoica et al., 2011), it may thus follow that a model that mimics constitutive mTORC1 activation, at least in one of its downstream signaling branches (such as the Eif4ebp2 KO mice), may result in enhanced plasticity and memory formation. Indeed, early-long term potentiation (E-LTP) in the CA1 region of the hippocampus, which is relevant for memory encoding, is exacerbated in Eif4ebp2 KO mice, and this is sensitive to protein synthesis and transcription inhibitors (Banko et al., 2005). However, late-LTP (L-LTP), induced by stronger stimulation (either 4 HFS or 4 TBS trains), is absent/occluded in Eif4ebp2 KO mice. Moreover, Eif4ebp2 KO mice are impaired in long-term contextual fear memory test and Morris water maze, although their memory for cued-fear conditioning is intact (Banko et al., 2005). Eif4ebp2 KO mice also show impaired hippocampal-dependent working memory in the T-maze spontaneous alternation (Banko et al., 2007). Eif4ebp2 KO mice do not have any exploratory/ambulatory alteration in the open field but have impaired motor learning and compromised motor coordination and balance (Banko et al., 2007). They do not show any impairment in step-through passive avoidance, or anxiety in the elevated plus maze (Banko et al., 2007). These results indicate that the absence of this translation repressor is necessary for proper memory encoding/retrieval. These effects on cognition may also be the result of a faulty developmental process due to the continuous absence of 4E-BP2 in Eif4ebp2 KO mice.
Importantly, Eif4ebp2 KO mice also present exacerbated chemically induced hippocampal LTD (Banko et al., 2006). This form of plasticity, induced by the type I mGluR agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), normally induces 4E-BP phosphorylation and eIF4F complex activation (Banko et al., 2006). Further characterization of this phenotype revealed that anisomycin, a protein synthesis inhibitor, can normalize but not block LTD in 4E-BP2 KO mice (Aguilar-Valles et al., 2015). Intriguingly, synaptically induced LTD, which also depends on protein translation, was completely absent in 4E-BP2 KO mice (Aguilar-Valles et al., 2015). The reason behind these mechanistic differences between chemically and electrically induced hippocampal LTD remains unexplored. Furthermore, it is still unclear how these effects on LTD may impact hippocampal-dependent cognitive processing. These findings are also partly divergent from those in the Fmr1 y/- mice, where chemically induced hippocampal LTD is also exacerbated (Huber, Kayser, & Bear, 2000) but is protein synthesis independent (i.e., insensitive to anisomycin; Hou et al., 2006). Adding to the confusion, a recent study showed that hippocampal mGluR-LTD (both chemically and synaptically induced) is normal in mice in which Raptor was knocked out in excitatory cells (Zhu, Chen, Mays, Stoica, & Costa-Mattioli, 2018). It still remains to be investigated whether the mTORC1-4E-BP pathway in inhibitory interneurons plays any role in the induction of mGluR-LTD.
Outside the hippocampus, 4E-BP2 appears to have a different role in memory formation; indeed, Eif4ebp2 KO mice demonstrated an enhanced performance in a conditioned taste aversion task by avoiding the saccharin and NaCl solutions to a higher degree than wild-types following a one trial pairing of saccharin or NaCl with LiCl (Banko et al., 2007). This type of conditioned learning involves the amygladar complex, the insular cortex, and the reward circuitry (Yamamoto & Yasoshima, 2007), suggesting that 4E-BP2 in other brain circuits can be acting as a physiological brake in the formation of learning.
Roles of 4E-BPs in Psychiatric Disorders
Substance abuse models. Most studies analyzing the role of mTORC1 signaling on the behavioral effects of drugs of abuse have focused on determining the activation (phosphorylation) of elements of this signaling pathway, as well as the effect of rapamycin. To date, there is no study on the direct effects of the 4E-BPs on addiction pathophysiology.
For example, several studies have shown that the psychostimulant cocaine regulates mTOR signaling in the reward circuitry, particularly the nucleus accumbens (Bailey, Ma, & Szumlinski, 2012; Sutton & Caron, 2015; Wu, McCallum, Glick, & Huang, 2011), and that this is important for some of the behavioral effects of this psychostimulant. Furthermore, activation of dopamine receptor 1 (D1R) is involved in the induction of mTORC1 activation and 4E-BP phosphorylation in the NAc (Sutton & Caron, 2015). Systemic injection of rapamycin blocked the expression of cocaine-induced locomotion (and sensitization) and conditional place preference (Bailey et al., 2012; James et al., 2014; Wu et al., 2011), and knockout of Mtor or Raptor in D1R expressing neurons reduced the locomotor response to acute cocaine treatment (Sutton & Caron, 2015). Infusions of rapamycin in the NAc have been shown to block the development of methamphetamine-induced conditional place preference (Narita et al., 2005).
In addition to psychostimulants, alcohol administration has also been shown to activate mTORC1-mediated signaling in the NAc of mice, including phosphorylation of 4E-BPs, and that rapamycin treatment decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking (Neasta, Ben Hamida, Yowell, Carnicella, & Ron, 2010). Morphine also activates mTORC1 in the VTA (Mazei-Robison et al., 2011), but it remains undetermined whether 4E-BP-dependent translational control of gene expression plays any role in the synaptic and behavioral neuroadaptations to this drug of abuse.
In contrast, amphetamine administration does not affect mTORC1 signaling (Biever et al., 2016); thus, the activation of mTORC1 signaling may not be a common mechanism shared by all psychostimulants or in general drugs of abuse. However, many studies have successfully used rapamycin to temper the effects of drugs of abuse, suggesting a key role for mTORC1 in reward and relapse behaviors.
Depressive disorders. Decreases in mTORC1 activation are observed in several models of depressive-like behaviors induced by chronic stress, including inescapable shock exposure (Li et al., 2010) or three weeks of chronic-unpredictable stress (Li et al., 2011). In addition, REDD1 (regulated in development and DNA damage response 1), an inhibitor of mTORC1 signaling (Katiyar et al., 2009), is increased by stress, and its overexpression in the mPFC is sufficient to produce synapse loss and depressive-like behavior (Ota et al., 2014). REDD1 is also found to be increased in postmortem tissue from individuals with depression, consistent with the possibility that REDD1 could contribute to neuronal atrophy and depressive behaviors in patients (Ota et al., 2014).
Consistently, several anti-depressant treatments produce an increase in mTORC1 activation and 4E-BP phosphorylation, including serotonin reuptake inhibitors (X. L. Liu et al., 2015; Park et al., 2014) and NMDA blocker such as ketamine (Li et al., 2010; Paul et al., 2014) and MK-801 (Yoon et al., 2008). mTOR activation is required for ketamine’s behavioral antidepressant actions, as intracerebroventricular pre-treatment with rapamycin blocks ketamine induced synaptic molecular changes and antidepressant actions in mice (Li et al., 2010) and rats (Holubova et al., 2016).
Intriguingly, rapamycin has antidepressant effects on its own (Cleary et al., 2008; Zhou et al., 2013), suggesting that the role of mTORC1 and its downstream targets in depression pathophysiology and antidepressant treatment may be more complex than anticipated. In this regard, the mechanistic contribution of 4E-BPs in the development of stress-induced synaptic alterations, depression-like behaviors and the antidepressant effects of SSRIs and NMDA blockers remains to be elucidated.
Anti-psychotic treatments. A potential role for 4E-BPs in the mechanism of action of antipsychotic treatments exists, as 4E-BP phosphorylation is increased by the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, in primary striatal D2R-positive neurons (Bowling et al., 2014). Furthermore, haloperidol-induced increase in dendritic morphological complexity in D2R- positive neurons was 4E-BP dependent (Bowling et al., 2014), which coincided with marked changes in the pattern of protein synthesis, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery (Bowling et al., 2014).
As for depression, the role of 4E-BPs in schizophrenia pathophysiology and treatment may be more nuanced, since models of schizophrenia induced by chronic treatment with the NMDA antagonist, MK-801, also result in increased phosphorylation of 4E-BP in the rat prefrontal cortex (Yoon et al., 2008), and rapamycin treatment reversed cognitive and affective deficits caused by Disc1 knockdown (Zhou et al., 2013). Gene mutations in DISC1 (disrupted-in-schizophrenia 1) are linked to psychiatric illness, including bipolar disorder, and depression (St. Clair et al.).
4E-BPs in Neurodegenerative Diseases
Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism (Farrer, 2006), a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. In Drosophila, overexpression of the translation inhibitor Thor (4E-BP) can suppress all the pathologic phenotypes of mutants in park and Pink1, including degeneration of dopaminergic neurons (Tain et al., 2009). Consistently, 4E-BP was shown to be hyperphosphorylated by the most common cause of parkinsonism, dominant mutations in LRRK2 (Imai et al., 2008). These results remain to be verified in mammalian animal models and in tissue from patients bearing the mutations linked to Parkinson’s disease.
4E-BPs are a central mechanism in the control of cap-dependent translation in the brain. They are major players in the control of brain development, affecting cortical and hippocampal synaptic transmission, neuronal morphology and migration of neurons. A testament of their importance in neurodevelopment is the finding that the absence of 4E-BP2 results in autistic-like alterations, as well as major deficits in learning and memory and hippocampal plasticity. These effects occur through the regulation of several key mRNAs, such as the AMPA subunits GluA1 and GluA2, and the neuroligins 1-3. Furthermore, 4E-BPs are central in circadian rhythm regulation, and have potential roles in the pathophysiology and treatment of psychiatric (depressive disorders, schizophrenia) and neurodegenerative disorders (Parkinson’s). As such, their pharmacological targeting (either enhancement or inhibition) is a promising avenue for the treatment of psychiatric and neurological disorders.
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