Circuitry, plasticity and gene expression in a mouse model of Rett Syndrome

描述（由申请人提供）：Rett综合征是一种毁灭性的发育障碍，在大多数情况下是由于基因Mecp 2突变引起的。受影响的人失去或无法发展许多正常的语言，运动和认知能力。缺乏部分或全部基因的突变小鼠重现了人类疾病的许多特征。然而，Mecp2引起疾病的精确分子和细胞相互作用在很大程度上仍然未知。我们最近发现，缺乏正常Mecp2的小鼠由于兴奋和抑制之间平衡的变化而减少了皮质活动。我们还发现，基因表达在皮层神经元中发生了改变，但不同的基因组在不同的神经元细胞类型中受到影响。我们将通过检查其他几种细胞类型中的基因表达来确定Mecp2缺失的影响是否更普遍，并将确定哪些变化在发育中最早发生。Rett患者有严重的学习障碍，Mecp2突变小鼠显示突触可塑性改变。突触可塑性的缺陷可能是Mecp 2功能丧失的主要影响，也可能是脑回路变化的次要影响。为了在这些可能性之间做出决定，我们将在最小化回路中其他变化的潜在影响的条件下，检查单个突触连接的长时程增强和抑制。我们还将研究一种称为突触缩放的可塑性的稳态形式。这是一种可塑性机制，通常在面对不断变化的活动水平时保持皮层网络稳定。缩放的破坏可能导致Mecp2功能丧失后活动水平的改变。最后，我们将确定在完全缺乏Mecp 2的小鼠中观察到的基因表达和生理学变化是否也发生在仅缺乏一个Mecp 2拷贝的杂合子小鼠中。

DESCRIPTION (provided by applicant): Rett Syndrome is a devastating developmental disorder due in most cases to mutation of the gene Mecp2. Affected individuals lose or fail to develop many normal language, motor and cognitive abilities. Mutant mice lacking part or all of the gene recapitulate many features of the human disease. However, the precise molecular and cellular interactions by which Mecp2 causes disease remain largely unknown. We found recently that mice lacking normal Mecp2 have reduced cortical activity due to a shift in the balance between excitation and inhibition. We also found that gene expression is altered in cortical neurons, but that different sets of genes are affected in different neuronal cell types. We will determine if this effect of loss of Mecp2 is more general by examining gene expression in several other cell types and will identify which changes occur earliest in development. Rett patients have severe learning disabilities and Mecp2 mutant mice show altered synaptic plasticity. The defects in synaptic plasticity could be primary effects of loss of Mecp2 function, or could be secondary to changes in brain circuitry. In order to decide between these possibilities we will examine long- term potentiation and depression at individual synaptic connections under conditions that minimize the potential impact of other changes in the circuit. We will also examine a homeostatic form of plasticity called synaptic scaling. This is a plasticity mechanism that normally keeps cortical networks stable in the face of changing activity levels. Disruption of scaling could contribute to altered activity levels following loss of Mecp2 function. Finally, we will determine whether or not the changes in gene expression and physiology observed in mice that lack Mecp2 altogether, also occur in heterozygous mice that lack only one copy of Mecp2.