Cognitive and Sensorimotor Gating Impairments in Transgenic Mice Overexpressing the Schizophrenia Susceptibility Gene Tcf4 in the Brain
Cognitive and Sensorimotor Gating Impairments in Transgenic Mice Overexpressing the Schizophrenia Susceptibility Gene Tcf4 in the Brain
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DOI：
10.1016/j.biopsych.2010.03.015
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发表时间：
2010-07-01
影响因子：
10.6
通讯作者：
Rossner, Moritz J.
中科院分区：
文献类型：
--
作者：
Brzozka, Magdalena M.;Radyushkin, Konstantin;Rossner, Moritz J.
背景资料：几个大的全基因组关联研究的综合分析确定了碱性螺旋-环-螺旋（bHLH）转录因子TCF 4作为最重要的精神分裂症易感基因之一。然而，它在成人大脑中的功能尚不清楚。TCF 4属于已知参与神经发育的E蛋白亚家族。Tcf 4的信使RNA表达在成年小鼠脑中持续存在，表明其在成年神经系统中具有功能。TCF 4无效突变小鼠围产期死亡，人类TCF 4的单倍不足导致严重的智力迟钝。方法：为了研究TCF 4在成人中枢神经系统中的可能功能，我们产生了转基因小鼠，适度过表达TCF 4出生后在大脑中，以减少可能干扰成人大脑功能的发育影响的风险。Tcf 4转基因小鼠的特点与分子，组织学和行为的methods.Results：Tcf 4转基因小鼠显示深刻的赤字，在上下文和线索的恐惧条件反射和感觉运动门控。此外，我们表明，TCF 4与神经原性bHLH因子NEUROD和NDRF在体内相互作用。分子分析揭示了动态昼夜失调的神经元bHLH因子在成人hippocamps.Conclusions：我们得出结论，TCF 4可能与其他神经元bHLH转录因子的行为，有助于高阶认知加工。Tcf 4在大脑中的中度转录失调干扰认知功能，并可能改变小鼠的昼夜节律过程。这些观察首次提供了对TCF 4在成人大脑中的生理功能及其对神经精神疾病状况的可能贡献的见解。
Background: The combined analysis of several large genome-wide association studies identified the basic helix-loop-helix (bHLH) transcription factor TCF4 as one of the most significant schizophrenia susceptibility genes. Its function in the adult brain, however, is not known. TCF4 belongs to the E-protein subfamily known to be involved in neurodevelopment. The messenger RNA expression of Tcf4 is sustained in the adult mouse brain, suggesting a function in the adult nervous system. Tcf4 null mutant mice die perinatally, and haploinsufficiency of TCF4 in humans causes severe mental retardation.Methods: To investigate the possible function of TCF4 in the adult central nervous system, we generated transgenic mice that moderately overexpress TCF4 postnatally in the brain to reduce the risk of developmental effects possibly interfering with adult brain functions. Tcf4 transgenic mice were characterized with molecular, histological, and behavioral methods.Results: Tcf4 transgenic mice display profound deficits in contextual and cued fear conditioning and sensorimotor gating. Furthermore, we show that TCF4 interacts with the neurogenic bHLH factors NEUROD and NDRF in vivo. Molecular analyses revealed the dynamic circadian deregulation of neuronal bHLH factors in the adult hippocampus.Conclusions: We conclude that TCF4 likely acts in concert with other neuronal bHLH transcription factors contributing to higher-order cognitive processing. Moderate transcriptional deregulation of Tcf4 in the brain interferes with cognitive functions and might alter circadian processes in mice. These observations provide insight for the first time into the physiological function of TCF4 in the adult brain and its possible contributions to neuropsychiatric disease conditions.