Exaggerated translation causes synaptic and behavioural aberrations associated with autism - PubMed (original) (raw)

. 2013 Jan 17;493(7432):411-5.

doi: 10.1038/nature11782. Epub 2012 Dec 23.

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Exaggerated translation causes synaptic and behavioural aberrations associated with autism

Emanuela Santini et al. Nature. 2013.

Abstract

Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. eIF4E transgenic mice exhibit increased eIF4E/eIF4G interactions and exaggerated cap-dependent translation

a, eIF4E transgenic mice (4E Tg) exhibit increased eIF4E expression in multiple brain regions. n=4 mice/genotype, *p<0.05 vs wild-type (WT), Student's _t_-test. b, 4E Tg mice exhibit normal expression of other translational control proteins. n=4 mice/genotype. *p<0.05 vs WT, Student's _t_-test. c, 4E Tg mice exhibit increased eIF4E/eIF4G interactions. Immunoprecipitation of eIF4E (left panel) and eIF4G (right panel). n=3 mice/genotype, *p<0.05 vs WT, Student's _t_-test. d, 4E Tg mice exhibit increased translation as measured with SUnSET (see Supplementary Methods). Vertical line traces of each autoradiogram are shown on the right. n=3 mice/genotype, *p<0.05 vs WT, Student's _t_-test. – represents a control sample without puromycin. All data are shown as mean ± SEM.

Figure 2

Figure 2. eIF4E transgenic mice exhibit ASD-like behaviors

eIF4E transgenic mice (4E Tg) were compared to wild-type (WT) littermates. a, Marble burying test: n=21–22 mice/genotype, ***p<0.001 and *p<0.05 vs WT, repeated measures (RM) ANOVA [time X genotype, F(2,46)=31.62, p< 0.001] followed by Bonferroni-Dunn test. b, Self-grooming test: n=12 mice/genotype, *p<0.05 vs WT, Student’s t_-test. c, Y-maze reversal task: n=21–22 mice/genotype, *p<0.05 and ***p<0.001 vs WT, RM ANOVA [time X genotype, F(5,138)=16.74, p< 0.001] followed by Bonferroni-Dunn test. d, Morris water maze (MWM) reversal learning: n=12–13 mice/genotype, *p<0.05 vs WT, RM ANOVA [time X genotype, F(3,92)=6.1, p< 0.001] followed by Bonferroni-Dunn test. e, Extinction of cued fear memory (15 CS/day represented as 3 CS/block): n=6 mice/genotype, *p<0.05 vs WT, RM ANOVA [day1: time X genotype, F(4,40)=5.73, p< 0.001; day2: time X genotype, F(4,40)=4.81, p< 0.01] followed by Bonferroni-Dunn test. f,g, Social behavior test: time spent interacting with either a stranger mouse f, or in the chambers g. n=6 mice/genotype, *p< 0.05 and °_p< 0.05 vs. WT, RM ANOVA [f: stimulus X genotype, F(1,10)=6.04, p< 0.05; g: stimulus X genotype, F(1,10)=6.12, p< 0.05] followed by Bonferroni-Dunn test. h, Reciprocal social interaction task: n=6 mice/genotype, *p<0.05 vs WT controls, Student's _t_-test. All data are shown as mean ± SEM.

Figure 3

Figure 3. eIF4E transgenic mice exhibit alterations in synaptic function, dendritic spine density, and synaptic plasticity

a, eIF4E transgenic mice (4E Tg) exhibit increased mEPSC frequency and b, increased mIPSC amplitude in layer 2/3 mPFC pyramidal neurons. n=27–30 neurons/genotype, *p<0.05 vs WT, Student's _t_-test. c,d, 4E Tg mice exhibit increased dendritic spine density in layer 2/3 mPFC pyramidal neurons. High-magnification images c, and quantification d, of spiny dendrites from wild-type (WT) and 4E Tg mice. n= 12 neurons/genotype, *p<0.05 vs WT, Student's _t_-test. Scale bar = 2 µm. e, 4E Tg mice exhibit enhanced striatal LTD. n=13 slices from 8 mice/genotype. f, 4E Tg mice exhibit enhanced hippocampal mGluR-LTD. n=15 slices from 8 mice/genotype. g, h, 4EGI-1 normalizes enhanced striatal LTD displayed by 4E Tg mice h, without impacting LTD in WT mice g. n=18 slices from 9 mice/genotype/treatment. All field recordings were analyzed with repeated measure ANOVAs. Arrows indicate delivery of high-frequency stimulation (HFS). Solid bars indicate the duration of bath application of DHPG (10 µM, 10 min) and 4EGI-1 (100 µM, 45 min). Representative traces (right panels) showing fEPSP before (black) and 60 min after (red) HFS. All data are shown as mean ± SEM.

Figure 4

Figure 4. The cap-dependent translation inhibitor 4EGI-1 reverses ASD-like behaviors displayed by eIF4E transgenic mice

a, Treatment of eIF4E transgenic mice (4E Tg) with 4EGI-1 reduces the marble-burying behavior n=6 mice/genotype/treatment, **p< 0.01, *p< 0.05 vs. 4E Tg + vehicle, two-way repeated measures (RM) ANOVA [treatment X genotype, F(1,20)= 4.21, p< 0.05] followed by Bonferroni-Dunn test. b, 4EGI-1 improves the cognitive flexibility of 4E Tg mice in the Y-maze test. n=6–7 mice/genotype/treatment, **p< 0.01, *p< 0.05 vs. 4E Tg + vehicle, two-way RM ANOVA [treatment X genotype, F(1,21)=4.61, p< 0.05] followed by Bonferroni-Dunn test. c, 4EGI-1 improves social behavior of 4E Tg mice in the three-chamber arena test. n=6 mice/genotype/treatment, *p< 0.05 and °p< 0.05 vs. 4E Tg + vehicle, two-way RM ANOVA [treatment X genotype, F(1,20)=6.26, p< 0.05] followed by Bonferroni-Dunn test. d, 4EGI-1decreases the enhanced eIF4E/eIF4G interactions in 4E Tg mice. Immunoprecipitation (IP) of eIF4E in the striatum. n=4 mice/genotype, *p<0.05 and °p<0.05 vs vehicle-treated wild-type (WT) and 4E Tg, respectively, two-way ANOVA, followed by Bonferroni-Dunn test. e, 4EGI-1 normalizes the exaggerated cap-dependent translation in 4E Tg mice as measured with SUnSET. The last WT sample represents a control without puromycin. *p<0.05 and °p<0.05 vs vehicle-treated WT and 4E Tg, respectively, two-way ANOVA, followed by Bonferroni-Dunn test. All data are shown as mean ± SEM.

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