Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism.
Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism.
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DOI：
10.1186/s13041-016-0192-8
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发表时间：
2016-01-27
期刊：
影响因子：
3.6
通讯作者：
Schwaller B
中科院分区：
文献类型：
--
作者：
Filice F;Vörckel KJ;Sungur AÖ;Wöhr M;Schwaller B
据报道，在几种自闭症谱系障碍（ASD）小鼠模型中，小清蛋白（PV）免疫反应性（PV+）GABA能中间神经元的数量减少或PV免疫反应性降低。这包括Shank突变小鼠，其中SHANK是人类ASD中最重要的突变基因家族之一。在Pvalb基因的杂合（PV+/-）小鼠中获得了类似的发现，其显示出稳健的ASD样表型。在这里，我们解决的问题，是否观察到的PV免疫反应性的减少是PV表达水平的降低和/或损失的PV表达GABA中间神经元亚群以下称为“Pvalb神经元”的结果。这两种替代方案具有重要意义，因为它们可能导致对兴奋/抑制平衡的相反作用，PV表达降低导致抑制增强，但Pvalb神经元亚群的损失导致抑制降低。体视学用于确定ASD相关脑区中Pvalb神经元的数量，包括PV-/-、PV+/-、Shank 1-/-和Shank 3B-/-小鼠的内侧前额叶皮质、体感皮质和纹状体。作为鉴定Pvalb神经元的第二个标志物，我们使用了野豌豆凝集素（VVA），一种识别包裹Pvalb神经元的特定细胞外基质的凝集素。分别通过Western印迹分析和qRT-PCR定量测定PV蛋白和Pvalb mRNA水平。我们对不同脑区总细胞数的分析表明，在所有情况下观察到的“PV+神经元减少”，即，在PV+/-、Shank 1-/-和Shank 3B-/-小鼠中，由于Pvalb mRNA和PV蛋白的减少，没有任何迹象表明神经元细胞减少/Pvalb神经元损失（由VVA+神经元数量不变证明）。我们的研究结果表明，PV系统可能代表了某些形式的ASD的收敛下游终点，由于PV的下调，兴奋/抑制平衡向增强抑制转移，是未来药物干预的有希望的靶点。因此，测试旨在恢复正常PV蛋白表达水平和/或Pvalb神经元功能的方法是否可以逆转小鼠中的ASD相关表型似乎是必要的，并且可能为新的治疗性治疗策略铺平道路。
A reduction of the number of parvalbumin (PV)-immunoreactive (PV+) GABAergic interneurons or a decrease in PV immunoreactivity was reported in several mouse models of autism spectrum disorders (ASD). This includes Shank mutant mice, with SHANK being one of the most important gene families mutated in human ASD. Similar findings were obtained in heterozygous (PV+/-) mice for the Pvalb gene, which display a robust ASD-like phenotype. Here, we addressed the question whether the observed reduction in PV immunoreactivity was the result of a decrease in PV expression levels and/or loss of the PV-expressing GABA interneuron subpopulation hereafter called “Pvalb neurons”. The two alternatives have important implications as they likely result in opposing effects on the excitation/inhibition balance, with decreased PV expression resulting in enhanced inhibition, but loss of the Pvalb neuron subpopulation in reduced inhibition. Stereology was used to determine the number of Pvalb neurons in ASD-associated brain regions including the medial prefrontal cortex, somatosensory cortex and striatum of PV-/-, PV+/-, Shank1-/- and Shank3B-/- mice. As a second marker for the identification of Pvalb neurons, we used Vicia Villosa Agglutinin (VVA), a lectin recognizing the specific extracellular matrix enwrapping Pvalb neurons. PV protein and Pvalb mRNA levels were determined quantitatively by Western blot analyses and qRT-PCR, respectively. Our analyses of total cell numbers in different brain regions indicated that the observed “reduction of PV+ neurons” was in all cases, i.e., in PV+/-, Shank1-/- and Shank3B-/- mice, due to a reduction in Pvalb mRNA and PV protein, without any indication of neuronal cell decrease/loss of Pvalb neurons evidenced by the unaltered numbers of VVA+ neurons. Our findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD, with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV being a promising target for future pharmacological interventions. Testing whether approaches aimed at restoring normal PV protein expression levels and/or Pvalb neuron function might reverse ASD-relevant phenotypes in mice appears therefore warranted and may pave the way for novel therapeutic treatment strategies.