Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, United States; Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States.
Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX 77807, United States.
Brain Res. 2022 Nov 15;1795:148060. doi: 10.1016/j.brainres.2022.148060. Epub 2022 Aug 27.
Fragile X syndrome (FXS), a leading monogenic cause of autism spectrum disorders (ASDs), typically occurs as the result of a mutation silencing the Fmr1 gene, preventing production of the fragile X messenger ribonucleoprotein (FMRP). FXS is characterized, in part, by hyperactivity, impaired behavioral flexibility, and the development of repetitive, or stereotyped, behaviors. While these phenotypes are influenced by striatal activity, few studies have examined FXS or FMRP in the context of striatal function. Here, we report enhanced repetitive behaviors in Fmr1 knockout (KO) compared to wild type (WT) mice according to multiple measures, including quantity and intensity of stereotypic behaviors in an open field and nose poking activity in an unbaited hole board test. However, using a baited version of the hole board assay, we see that KO mice do show some behavioral flexibility in that they make changes in their nose poking behavior following familiarization with an appetitive bait. By contrast, repeated exposure to cocaine (15 mg/kg) promotes repetitive behavior in both WT and KO mice, in a manner mostly independent of genotype. Branch length alterations in medium spiny neurons (MSNs) of the dorsolateral striatum (DLS) are similar between WT cocaine-treated and KO saline-treated mice, possibly suggesting shared synaptic mechanisms. Overall, we suggest that scoring open field behavior is a sensitive measure for repetitive sensory-motor behaviors in Fmr1 KO mice. In addition, our findings show that synaptic contacts onto MSNs in the DLS should be examined in conjunction with measures of stereotypical behavior.
脆性 X 综合征 (FXS) 是自闭症谱系障碍 (ASD) 的主要单基因病因之一，通常是由于沉默 Fmr1 基因的突变导致的，从而阻止了脆性 X 信使核糖核蛋白 (FMRP) 的产生。FXS 的部分特征是活动过度、行为灵活性受损以及重复性或刻板性行为的发展。虽然这些表型受纹状体活性的影响，但很少有研究在纹状体功能的背景下研究 FXS 或 FMRP。在这里，我们报告了 Fmr1 敲除 (KO) 小鼠与野生型 (WT) 小鼠相比，根据多种测量方法，包括在开阔场中的刻板行为的数量和强度以及在无诱饵孔板测试中的鼻戳活动，表现出增强的重复性行为。然而，使用诱饵版的孔板测定法，我们发现 KO 小鼠在某种程度上确实表现出了行为灵活性，因为它们在熟悉了有吸引力的诱饵后，改变了鼻戳行为。相比之下，重复暴露于可卡因 (15mg/kg) 可促进 WT 和 KO 小鼠的重复性行为，这种方式在很大程度上与基因型无关。背外侧纹状体 (DLS) 中的中脑皮质神经元 (MSNs) 的分支长度改变在 WT 可卡因处理和 KO 盐水处理的小鼠之间相似，这可能表明存在共同的突触机制。总的来说，我们认为对开阔场行为的评分是评估 Fmr1 KO 小鼠重复性感觉运动行为的敏感指标。此外，我们的研究结果表明，在 DLS 中的 MSNs 上的突触接触应该与刻板行为的测量一起进行检查。
