1.NMDA受体NR2A和NR2B亚单位在癫痫发生过程中不同作用的研究 2.丝氨酸—苏氨酸激酶9（STK9）在大脑神经元迁移中的作用
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摘要
癫痫病(Epilepsy)是一种危及人类健康的常见疾病,目前对癫痫病的治疗还缺乏有效手段。研究表明NMDA受体在癫痫病的产生过程中起着至关重要的作用,NMDA受体非选择性拮抗剂MK801能够抑制癫痫持续状态( Status Epilepticus SE )引起的细胞损伤和癫痫病的产生。NMDA受体由NR1和NR2两种亚基构成,NR2亚基又分为NR2A, NR2B, NR2C, NR2D四种亚单位,不同的亚单位在大脑中的分布以及在生理和病理情况下作用是不同的。本研究的目的是探讨NMDA受体NR2亚基中NR2A和NR2B亚单位在癫痫病产生过程中的不同作用。实验表明NR2A和NR2B亚单位分别与不同的信号通路相关,阻断NR2A亚单位后能够抑制兴奋性突触传递引起的BDNF表达上升,而阻断NR2B亚单位后能够抑制兴奋性突触传递引起的ERK1/2磷酸化水平的上升。在模拟人类颞叶癫痫的两种经典的动物模型-电刺激点燃(Kindling Model)和匹罗卡品诱导癫痫(Pilocarpine Model)的大鼠模型中,分别给大鼠NMDA受体非选择性抑制剂MK801,NR2A选择性抑制剂NVP-AAM077,NR2B选择性抑制剂Ifenprodil后,观察各拮抗剂对大鼠癫痫产生和癫痫持续状态对大鼠神经元的损伤是否存在差异。实验结果表明:在Kindling模型中MK801,NVP-AAM077可以延缓癫痫产生的过程,而Ifenprodil对这一过程没有明显抑制性作用。在匹罗卡品诱导癫痫的大鼠模型中,MK801、NVP-AAM077和Ifenprodil都可以保护癫痫持续状态对大鼠神经元的损伤。MK801和NVP-AAM077可以抑制自发性癫痫的产生,而Ifenprodil对此没有作用。本研究结果显示在癫痫病中NR2A和NR2B亚单位都参与了癫痫持续状态对大鼠神经元的损伤,而NR2A和NR2B亚单位在癫痫产生过程中发挥不同的作用,这可能与两种不同的亚单位激活不同基因和信号途径有关。该发现为临床研制抗癫痫的药物提供了新的靶点。
Rett综合征((RTT, OMIM 312750)是一种严重影响儿童神经发育的遗传疾病,患者出现严重的智力低下,该疾病主要累及女性,女孩中发病率约为1/10 000～1/15 000。Rett综合征包括典型和非典型两类。最近研究表明丝氨酸-苏氨酸激酶9 (Serine Threonine Kinase 9 STK9,又称为Cyclin Dependent Kinase-Like 5 CDKL5)和非典型Rett综合征发病相关。临床筛查非典型Rett综合征时发现病人中STK9基因存在错义突变,无义突变或移码突变,造成氨基酸替代或翻译提前终止,从而使得该基因功能丧失,导致了非典型性Rett综合征,属于基因功能丧失(Loss of function)导致的遗传疾病。本研究中我们成功的从大鼠大脑cDNA文库中克隆了大鼠的STK9基因,并发现STK9基因存在两种不同形式的剪切体(STK9-S, STK9-L),不同的剪切体编码的蛋白在细胞中的分布不同:STK9-S主要分布于细胞的胞核内,STK9-L主要分布于细胞胞浆中。利用原位杂交技术发现STK9基因广泛的表达于各种组织中。在中枢神经系统STK9基因在胚胎早期就开始表达,在发育过程中逐渐增高,成年后表达水平下降。在胚胎期利用RNAi基因干扰技术结合子宫内胚胎电转急性敲减STK9基因后,发现皮层神经元的迁移受到影响,提示STK9基因可能在皮层神经元的迁移过程中起着重要的作用。本研究为今后进一步了解STK9基因在非典型性Rett综合征中致病机制打下了良好的基础。
Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and ERK1/2 activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, while inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.
Mutations in the CDKL5 gene (Cyclin Dependent Kinase-Like 5, also named as STK9, Serine Threonine Kinase 9) are associated with early-onset mental retardation and severe neurological symptoms. The clinical features meet the criteria for the early-onset of Rett syndrome, and suggest that CDKL5/STK9 plays important roles in brain development. Here we show that CDKL5/STK9 regulates neuronal migration. CDKL5/STK9 mRNA and protein were highly expressed in the developing rat brain and decreased rapidly in the adulthood. In vivo reduced amounts of STK9 caused inhibition of cortical neuronal migration. Our findings suggest that STK9 plays a critical role in neuronal migration during corticogenesis. Our studies together with the clinical findings shed light on the critical roles of STK9 in the atypical Rett syndrome.
Rett综合征((RTT, OMIM 312750)是一种严重影响儿童神经发育的遗传疾病,患者出现严重的智力低下,该疾病主要累及女性,女孩中发病率约为1/10 000～1/15 000。Rett综合征包括典型和非典型两类。最近研究表明丝氨酸-苏氨酸激酶9 (Serine Threonine Kinase 9 STK9,又称为Cyclin Dependent Kinase-Like 5 CDKL5)和非典型Rett综合征发病相关。临床筛查非典型Rett综合征时发现病人中STK9基因存在错义突变,无义突变或移码突变,造成氨基酸替代或翻译提前终止,从而使得该基因功能丧失,导致了非典型性Rett综合征,属于基因功能丧失(Loss of function)导致的遗传疾病。本研究中我们成功的从大鼠大脑cDNA文库中克隆了大鼠的STK9基因,并发现STK9基因存在两种不同形式的剪切体(STK9-S, STK9-L),不同的剪切体编码的蛋白在细胞中的分布不同:STK9-S主要分布于细胞的胞核内,STK9-L主要分布于细胞胞浆中。利用原位杂交技术发现STK9基因广泛的表达于各种组织中。在中枢神经系统STK9基因在胚胎早期就开始表达,在发育过程中逐渐增高,成年后表达水平下降。在胚胎期利用RNAi基因干扰技术结合子宫内胚胎电转急性敲减STK9基因后,发现皮层神经元的迁移受到影响,提示STK9基因可能在皮层神经元的迁移过程中起着重要的作用。本研究为今后进一步了解STK9基因在非典型性Rett综合征中致病机制打下了良好的基础。
Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and ERK1/2 activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, while inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.
Mutations in the CDKL5 gene (Cyclin Dependent Kinase-Like 5, also named as STK9, Serine Threonine Kinase 9) are associated with early-onset mental retardation and severe neurological symptoms. The clinical features meet the criteria for the early-onset of Rett syndrome, and suggest that CDKL5/STK9 plays important roles in brain development. Here we show that CDKL5/STK9 regulates neuronal migration. CDKL5/STK9 mRNA and protein were highly expressed in the developing rat brain and decreased rapidly in the adulthood. In vivo reduced amounts of STK9 caused inhibition of cortical neuronal migration. Our findings suggest that STK9 plays a critical role in neuronal migration during corticogenesis. Our studies together with the clinical findings shed light on the critical roles of STK9 in the atypical Rett syndrome.
引文
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