Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA.
J Neurosci Res. 2023 Aug;101(8):1236-1258. doi: 10.1002/jnr.25190. Epub 2023 Apr 7.
Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2 , Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying typical levels of perineuronal net expression in the barrel field subregion of the primary somatosensory cortex, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincides with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.
雷特综合征的特征是早期表现正常，随后女孩的运动和言语技能逐渐退化。人们认为 MECP2 蛋白的缺失导致了雷特综合征的表型。从典型发育轨迹到终生退化特征的具体潜在机制尚不清楚。缺乏既定的时间框架来研究女性小鼠模型中退化的分子、细胞和行为特征是一个主要因素。由于 X 染色体随机失活，雷特综合征女性患者和雷特综合征的女性小鼠模型（Mecp2 Het）中约有一半的细胞表达野生型 MECP2 蛋白的功能副本。由于 MECP2 的表达在出生后早期发育和经历中受到调节，我们对雌性 Het 小鼠初级体感皮层中野生型 MECP2 的表达进行了特征描述。在这里，我们报告了与年龄匹配的野生型对照相比，6 周龄青少年 Het 中非 PV 阳性神经元中的 MECP2 水平升高，而初级体感皮层桶状回亚区的周围神经网表达也具有典型水平，轻度触觉感知缺陷，以及有效的幼崽回收行为。相比之下，12 周龄成年 Het 表达的 MECP2 水平与年龄匹配的野生型小鼠相似，皮层周围神经网表达增加，并表现出明显的触觉感知缺陷。因此，我们确定了一套行为指标和细胞基底，用于研究雌性 Het 小鼠模型中特定时间的退化，这与野生型 MECP2 表达的变化相一致。我们推测，青少年 Het 中特定细胞类型中 MECP2 表达的过早增加可能在行为水平上提供代偿性益处，而随着时间的推移，无法进一步增加 MECP2 水平会导致退行性行为表型。
