Tbr2 deficiency in mitral and tufted cells disrupts excitatory-inhibitory balance of neural circuitry in the mouse olfactory bulb.
Tbr2 deficiency in mitral and tufted cells disrupts excitatory-inhibitory balance of neural circuitry in the mouse olfactory bulb.
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DOI：
10.1523/jneurosci.5746-11.2012
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发表时间：
2012-06-27
期刊：
影响因子：
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通讯作者：
Yoshihara Y
中科院分区：
文献类型：
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作者：
Mizuguchi R;Naritsuka H;Mori K;Mao CA;Klein WH;Yoshihara Y
嗅球（OB）是大脑中的第一个中继站，来自嗅觉上皮的气味信息在这里被整合，通过其内在的神经回路进行处理，并传送到更高的嗅觉中心。与对从鼻子到 OB 的嗅觉轴突连接的深刻机制见解相比，我们对 OB 内各种类型神经元之间功能神经回路形成的分子机制知之甚少。 T-box 转录因子 Tbr2 在大脑中各种类型的谷氨酸能兴奋性神经元中表达，包括 OB 投射神经元、二尖瓣和簇状细胞。在这里，我们生成了条件敲除小鼠，其中 Tbr2 基因在胚胎晚期的二尖瓣和簇状细胞中特异性失活。 Tbr2 缺陷导致细胞自主的分子表达变化，包括另一个 T 盒成员 Tbr1 的代偿性增加，以及伴随的囊泡谷氨酸转运蛋白 (VGluT) 亚型从 VGluT1 向 VGluT2 的转变。 Tbr2缺陷的二尖瓣和簇状细胞的树突形态和投影模式也表现出解剖学异常。此外，在小白蛋白、钙结合蛋白和 5T4 阳性 GABA 能中间神经元中观察到了几种非细胞自主表型。此外，二尖瓣/簇状细胞和 GABA 能中间神经元之间的树突状突触数量显着减少。在用气味剂刺激后，Tbr2条件敲除小鼠中大量的二尖瓣和簇状细胞被激活。这些结果表明，Tbr2 不仅是二尖瓣和簇状细胞正确分化所必需的，而且也是 OB 中功能性神经元回路的建立和维持对气味信息处理至关重要的兴奋-抑制平衡所必需的。
The olfactory bulb (OB) is the first relay station in the brain where odor information from the olfactory epithelium is integrated, processed through its intrinsic neural circuitry, and conveyed to higher olfactory centers. Compared with profound mechanistic insights into olfactory axon wiring from the nose to the OB, little is known about the molecular mechanisms underlying the formation of functional neural circuitry among various types of neurons inside the OB. T-box transcription factor Tbr2 is expressed in various types of glutamatergic excitatory neurons in the brain including the OB projection neurons, mitral and tufted cells. Here we generated conditional knockout mice in which the Tbr2 gene is inactivated specifically in mitral and tufted cells from late embryonic stages. Tbr2 deficiency caused cell-autonomous changes in molecular expression including a compensatory increase of another T-box member, Tbr1, and a concomitant shift of vesicular glutamate transporter (VGluT) subtypes from VGluT1 to VGluT2. Tbr2-deficient mitral and tufted cells also exhibited anatomical abnormalities in their dendritic morphology and projection patterns. Additionally, several non-cell-autonomous phenotypes were observed in parvalbumin-, calbindin-, and 5T4-positive GABAergic interneurons. Furthermore, the number of dendrodendritic reciprocal synapses between mitral/tufted cells and GABAergic interneurons was significantly reduced. Upon stimulation with odorants, larger numbers of mitral and tufted cells were activated in Tbr2 conditional knockout mice. These results suggest that Tbr2 is required for not only the proper differentiation of mitral and tufted cells, but also for the establishment of functional neuronal circuitry in the OB and maintenance of excitatory–inhibitory balance crucial for odor information processing.