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

Genes, Brain and Behavior - Tập 11 Số 5 - Trang 586-600 - 2012
Susan Goebel-Goody1, E. D. Wilson‐Wallis1, Sam Royston2, Stephanie Tagliatela2, Janice R. Naegele2, Paul J. Lombroso1
1Child Study Center, Yale University School of Medicine, New Haven, CT, USA;
2Department of Biology and Program in Neuroscience and Behavior, Wesleyan University, Middletown, CT, USA

Tóm tắt

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 shows that FMRP interacts with the transcript encoding striatal‐enriched protein tyrosine phosphatase (STEP; Ptpn5). STEP opposes synaptic strengthening and promotes synaptic weakening by dephosphorylating its substrates, including ERK1/2, p38, Fyn and Pyk2, and subunits of N‐methyl‐d‐aspartate (NMDA) and AMPA receptors. Here, we show that basal levels of STEP are elevated and mGluR‐dependent STEP synthesis is absent in Fmr1KO mice. 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 and assessed mice in a battery of behavioral tests. 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 and anxiety. Loss of STEP also corrected select nonsocial anxiety‐related behaviors in Fmr1KO mice, such as light‐side exploration in the light/dark box. Our findings indicate that genetically reducing STEP significantly diminishes seizures and restores select social and nonsocial anxiety‐related behaviors in Fmr1KO mice, suggesting that strategies to inhibit STEP activity may be effective for treating patients with FXS.

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Genes, Brain and Behavior

Tập 11 Số 5

586-600

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