Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Abstract

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.F ragile X syndrome (FXS) is the most common heritable form of intellectual disability and a leading genetic cause of autism. Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic movements, hyperactivity, seizures, and aggression, as well as social deficits typical of autism (1). FXS is caused by transcriptional silencing or mutation of the FMR1 gene encoding the RNA-binding protein, FMRP (fragile X mental retardation protein). FMRP binds to >1,000 mRNAs, including transcripts encoding both preand postsynaptic proteins important for synaptic function, and represses their translation via ribosome stalling (2). Loss of FMRP expression in fragile X syndrome would be expected to cause translational derepression of these target mRNAs.FMRP is strategically localized to dendrites, dendritic spines, axons, and cell bodies to control protein synthesis. Loss of FMRP causes enhanced protein synthesis, which can lead to altered spine morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked protein synthesis and impaired stimulus-induced protein synthesis are considered to be major contributors to the pathophysiology of fragile X (3-5). Increased protein synthesis has been demonstrated in whole-animal st...

Mechanistic Target of Rapamycin–Independent Antidepressant Effects of ( R )-Ketamine in a Social Defeat Stress Model

“…Both mTOR and extracellular signal-regulated kinase (ERK) are key signaling molecules in two prominent pathways that regulate protein synthesis (48,49). The current study was conducted to examine whether mTOR signaling and/or ERK signaling play a role in the mechanisms underlying the antidepressant actions of (R)-ketamine and (S)-ketamine in a chronic social defeat stress (CSDS) model of depression.…”

Effects of the presence and absence of amino acids on translation, signaling, and long‐term depression in hippocampal slices from Fmr1 knockout mice

“…There is cross‐talk and compensation between the Ras‐ERK and PI3K‐mTOR pathways (Mendoza et al ), so it is of interest to consider responses together. Moreover, the ERK pathway has been reported to be implicated in FXS (Osterweil et al ; Osterweil et al ; Sawicka et al ). In our experiment, we found a statistically significant main effect of amino acid condition such that total ERK was lower in AAS compared with AAR regardless of genotype or treatment (Table S1, Fig.…”

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…157 At the molecular level, generation of AGS likely involves the common signal pathways underlying other FXS phenotypes, because the frequency of AGS in Fmr1 knockout mice is reduced by correcting mGluR5 signaling 143,158 or ERK1/2 activity. 159,160 Although the AGS in Fmr1 knockout mice are frequently compared to epilepsy in FXS individuals, it is not clear that the underlying seizures are similar in humans and mice. 149 Moreover, the relationship between AGS and sound tolerance issues in FXS individuals has not been established, presenting questions for future research.…”