Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model

Abstract

Fragile X syndrome (FXS), the most common inherited form of intellectual disability and prevailing known genetic basis of autism, is caused by an expansion in the Fmr1 gene that prevents transcription and translation of fragile X mental retardation protein (FMRP). FMRP binds to and controls translation of mRNAs downstream of metabotropic glutamate receptor (mGluR) activation. Recent work identified striatal-enriched protein tyrosine phosphatase (STEP) as an FMRP target mRNA. STEP opposes synaptic strengthening and promotes synaptic weakening by dephosphorylating its substrates, including ERK1/2, p38, Fyn, Pyk2, and subunits of NMDA and AMPA receptors. Here we demonstrate that STEP translation is dysregulated in Fmr1KO mice, resulting in elevated basal levels of STEP with a concomitant loss of mGluR-dependent STEP translation. We hypothesized that the weakened synaptic strength and behavioral abnormalities reported in FXS may be linked to excess levels of STEP. To test this hypothesis, we reduced or eliminated STEP genetically in Fmr1KO mice. In addition to attenuating audiogenic seizures and seizure-induced c-Fos activation in the periaqueductal gray, genetically reducing STEP in Fmr1KO mice reversed characteristic social abnormalities, including approach, investigation, novelty-induced hyperactivity and anxiety. Loss of STEP also corrected select non-social anxiety-related behaviors in Fmr1KO mice, such as open arm exploration in the elevated plus maze. Our findings indicate that genetically reducing STEP significantly diminishes seizures and restores social and non-social anxiety-related behaviors in Fmr1KO mice, suggesting that strategies to inhibit STEP activity may be effective for treating patients with FXS.

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…In accordance with the human data, Fmr1 KO mice display enhanced susceptibility to audiogenic seizures (Bakker 1994;Musumeci et al 2000;Peier et al 2000;Chen and Toth 2001;Yan et al 2004Yan et al , 2005Min et al 2009;Liu et al 2011;Goebel-Goody et al 2012;Thomas et al 2012;Veeraragavan et al 2012;Osterweil et al 2013;Udagawa et al 2013). Although the severity of the phenotype may be affected by the genetic background (Table 1; Yan et al 2004), susceptibility to audiogenic seizures is the most consistent behavioral phenotype and is usually implemented to screen for potential drugs to ameliorate FXS.…”

“…The genetic cross of the APP KO with the Fmr1 KO lead to amelioration of cellular and behavioral FXS effects (Westmark et al 2011). Reduction of STEP (Goebel-Goody et al 2012), a target of FMRP, corrects some behavioral phenotypes of Fmr1 KO mice. Furthermore, the doubly mutant dfmr1 and futsch (a Map1b homolog and target of FMRP) in flies could rescue the synaptic defects in the neuromuscular junction and in the eye, but failed to rescue the locomotor activity (Zhang et al 2001).…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…Fmr1 KO mice have not been reported to display spontaneous seizures, but are more susceptible to audiogenic seizures, induced by exposure to a 125 decibel, high-intensity siren (48,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Audiogenic seizure vulnerability in Fmr1 KO mice may reflect seizure susceptibly in FXS, although audiogenic seizure severity in Fmr1 KO mice varied in degree depending on age and background strain (86,91,94,95).…”

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

“…Recently, the striatal enriched protein tyrosine phosphatase (STEP) has been shown to be upregulated in FXS, and genetic reduction of STEP diminished seizures and restored selected social and nonsocial anxiety-related behaviors in the Fmr1 KO mice (94). Because STEP acts on at least three molecules (ERK1/2, NMDA, and AMPA) affected in FXS, strategies to inhibit STEP activity may be considered for treating patients with FXS.…”