Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes
Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes
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DOI：
10.1073/pnas.0904636106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Penzes, Peter
中科院分区：
文献类型：
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作者：
Cahill, Michael E.;Xie, Zhong;Penzes, Peter
树突棘的形态发生有助于大脑功能、认知和行为，并在精神障碍中改变。Kalirin是一种针对RAC样GTP酶的脑特异性鸟嘌呤核苷酸交换因子，是脊柱形态发生的关键调节因子。在这里，我们显示KALRN基因敲除小鼠的大脑皮质中有特异性的减少，但没有海马体、rac1信号和脊柱密度的减少，并且表现出皮质谷氨酸能传递的减少。这些小鼠在工作记忆、社交能力和脉搏前抑制方面表现出强烈的缺陷，与之平行的是氯氮平以卡利林依赖的方式可逆的运动多动。这些赤字中有几个是延迟的，与年龄有关。因此，我们的研究将脊柱形态发生信号与年龄相关、延迟、疾病相关的表型联系起来，包括认知功能障碍。
Dendritic spine morphogenesis contributes to brain function, cognition, and behavior, and is altered in psychiatric disorders. Kalirin is a brain-specific guanine-nucleotide exchange factor (GEF) for Rac-like GTPases and is a key regulator of spine morphogenesis. Here, we show that KALRN-knockout mice have specific reductions in cortical, but not hippocampal, Rac1 signaling and spine density, and exhibit reduced cortical glutamatergic transmission. These mice exhibit robust deficits in working memory, sociability, and prepulse inhibition, paralleled by locomotor hyperactivity reversible by clozapine in a kalirin-dependent manner. Several of these deficits are delayed and age-dependent. Our study thus links spine morphogenic signaling with age-dependent, delayed, disease-related phenotypes, including cognitive dysfunction.