PDF(Pubmed)
Abstract：
The homozygous Bronx waltzer (bv) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in bv/bv mice. However, in situ hybridization revealed that Srrm4 is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the bv/bv cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABAA receptors revealed increased excitability in bv/bv mice, although no gross change occurred in the expression of an Srrm4-downstream gene, Kcc2, which regulates chloride flux upon GABAergic transmission. These findings suggest that the bv-associated Srrm4 mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in bv/bv mice.
摘要：
纯合子布朗克斯·华策（BV）小鼠，这表明听力受损，还表现出焦虑，伴有皮质小清蛋白（PV）阳性GABA能中间神经元的减少。最近,在bv小鼠中发现了剪接因子Ser/Arg重复矩阵4（Srrm4）的突变。然而,Srrm4突变对焦虑的细胞影响尚不清楚.这里,我们检验了我们的假设，即bv突变体主要通过细胞内在病理影响中间神经元，导致中间神经元减少，从而引起焦虑。我们发现,在bv/bv小鼠中,焦虑在6周龄时变得明显。然而,原位杂交显示Srrm4在中间神经元中不表达，而是在锥体神经元中占主导地位。此外,当焦虑变得明显时，bv/bv皮层中PV阳性GABA能中间神经元的数量没有减少。然而,同时存在来自中间神经元的GABA能传递的电生理异常。GABAA受体的药理学阻断显示bv/bv小鼠的兴奋性增加，尽管Srrm4下游基因的表达没有发生重大变化，Kcc2，调节GABA能传递时的氯化物通量。这些发现表明，bv相关的Srrm4突变主要涉及中枢神经系统的突触后GABA能传递，这可能与bv/bv小鼠的焦虑表型有关。
