Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.
Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.
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自闭症小脑中间神经元中 GAD67 mRNA 表达增加：对浦肯野细胞功能障碍的影响。
DOI：
10.1002/jnr.21520
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发表时间：
2008
影响因子：
4.2
通讯作者：
Blatt,GeneJ
中科院分区：
文献类型：
--
作者：
Yip,Jane;Soghomonian,Jean-Jacques;Blatt,GeneJ
据广泛报道，在自闭症中，浦肯野细胞（PC）的数量减少，最近还观察到浦肯野细胞中谷氨酸脱羧酶67（GAD67）mRNA的表达减少。然而，自闭症文献并未涉及浦肯野细胞的关键 GABA 能输入。小脑皮质分子层中的抑制性篮状细胞和星状细胞中间神经元为浦肯野细胞提供直接关键的 GABA 能输入，并可能有效影响浦肯野细胞向小脑深部核团的输出。我们研究了两种类型的中间神经元合成 γ-氨基丁酸 (GABA) 的能力，这些中间神经元支配自闭症患者小脑半球后外侧的剩余 PC。 GAD67mRNA（GABA 关键合成酶的异构体之一）的水平通过原位杂交在自闭症和年龄匹配对照的大脑中在单细胞水平上进行了定量。美国国立卫生研究院成像系统显示，与八个对照大脑相比，八个自闭症大脑的篮子细胞中 GAD67mRNA 的表达显着上调，达 28%（每个细胞的平均值 ± SEM 像素，分别为 1.03 ± 0.05 与 0.69 ± 0.05；独立测试 P< 0.0001）。星状细胞显示GAD67mRNA水平小幅增加的趋势，但这并未达到显着水平。结果表明，篮细胞可能对自闭症 PC 提供增强的 GABA 前馈抑制，直接影响齿状核中目标神经元的 PC 输出，并可能破坏其在自闭症个体关键运动和/或认知行为中的调节作用。 © 2007 Wiley-Liss, Inc.
It has been widely reported that in autism, the number of Purkinje cells (PCs) is decreased, and recently, decreased expression of glutamic acid decarboxylase 67 (GAD67) mRNA in Purkinje cells also has been observed. However, the autism literature has not addressed key GABAergic inputs into Purkinje cells. Inhibitory basket and stellate cell interneurons in the molecular layer of the cerebellar cortex provide direct key GABAergic input into Purkinje cells and could potently influence the output of Purkinje cells to deep cerebellar nuclei. We investigated the capacity for interneuronal synthesis of gamma‐amino butyric acid (GABA) in both types of interneurons that innervate the remaining PCs in the posterolateral cerebellar hemisphere in autism. The level ofGAD67mRNA, one of the isoforms of the key synthesizing enzymes for GABA, was quantified at the single‐cell level using in situ hybridization in brains of autistic and aged‐matched controls. The National Institutes of Health imaging system showed that expression ofGAD67mRNA in basket cells was significantly up‐regulated, by 28%, in eight autistic brains compared with that in eight control brains (mean ± SEM pixels per cell, 1.03 ± 0.05 versus 0.69 ± 0.05, respectively;P< 0.0001 by independentttest). Stellate cells showed a trend toward a small increase inGAD67mRNA levels, but this did not reach significance. The results suggest that basket cells likely provide increased GABAergic feed‐forward inhibition to PCs in autism, directly affecting PC output to target neurons in the dentate nucleus and potentially disrupting its modulatory role in key motor and/or cognitive behaviors in autistic individuals. © 2007 Wiley‐Liss, Inc.