Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.
Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.
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DOI：
10.1093/cercor/bhv274
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
de Curtis I
中科院分区：
文献类型：
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作者：
Pennucci R;Talpo F;Astro V;Montinaro V;Morè L;Cursi M;Castoldi V;Chiaretti S;Bianchi V;Marenna S;Cambiaghi M;Tonoli D;Leocani L;Biella G;D'Adamo P;de Curtis I
Rac GTP酶通过影响GABA能前体的早期发育和迁移来调节皮质/海马GABA能中间神经元的发育。我们已经解决了Rac 1和Rac 3蛋白在海马中间神经元成熟后期的功能。我们观察到条件Rac 1和完全Rac 3敲除小鼠之间的特定表型差异。与Rac 3缺失相比，Rac 1缺失导致更大的全身性多动和认知障碍。这种表型与Rac 1突变体中抑制回路的更明显的功能障碍相匹配，表现出更高的兴奋性和CA海马锥体神经元中自发抑制电流的降低。形态学分析证实了差异修改的抑制电路：删除任何Rac引起类似的减少小白蛋白阳性抑制终端的锥体层。有趣的是，大麻素受体-1-阳性末端仅在Rac 1缺失小鼠的CA 1中强烈增加。这种增加可能是该突变体中更强的电生理缺陷的基础。因此，与大麻素受体拮抗剂孵育部分挽救了Rac 1突变体锥体细胞中自发抑制电流的减少。我们的研究结果表明，Rac 1和Rac 3在GABA能回路的形成中具有独立的作用，正如其缺失对特定中间神经元群体的晚期成熟的差异效应所突出的那样。
Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.