Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.
Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.
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DOI：
10.1111/j.1601-183x.2012.00781.x
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Lombroso PJ
中科院分区：
文献类型：
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作者：
Goebel-Goody SM;Wilson-Wallis ED;Royston S;Tagliatela SM;Naegele JR;Lombroso PJ
脆性X综合征（FXS）是最常见的智力残疾遗传形式，也是自闭症的普遍已知遗传基础，它是由Fmr1基因的扩增引起的，该基因阻止了脆性X智力迟钝蛋白（FMRP）的转录和翻译。FMRP结合并控制代谢谷氨酸受体（mGluR）激活下游mrna的翻译。最近的研究发现纹状体富集蛋白酪氨酸磷酸酶（STEP）是FMRP靶mRNA。STEP通过其底物（包括ERK1/2、p38、Fyn、Pyk2以及NMDA和AMPA受体亚基）的去磷酸化来抑制突触增强并促进突触减弱。本研究表明，STEP翻译在Fmr1KO小鼠中失调，导致STEP基础水平升高，同时伴有mglur依赖的STEP翻译缺失。我们假设FXS中报告的突触强度减弱和行为异常可能与STEP水平过高有关。为了验证这一假设，我们从基因上减少或消除了Fmr1KO小鼠的STEP。除了减轻听源性癫痫发作和癫痫引起的导水管周围灰质c-Fos激活外，Fmr1KO小鼠中遗传减少STEP还逆转了特征性社交异常，包括走近、调查、新奇性多动和焦虑。STEP缺失还纠正了Fmr1KO小鼠的非社交焦虑相关行为，如在高架迷宫中张开手臂探索。我们的研究结果表明，基因上减少STEP可以显著减少Fmr1KO小鼠的癫痫发作，并恢复社交和非社交焦虑相关行为，这表明抑制STEP活性的策略可能对治疗FXS患者有效。
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.