Genetic Studies of the Synapse

 描述（由申请人提供）：神经发生对于胚胎发生期间神经系统的生成以及促进成年海马回路可塑性（涉及将相似体验转化为独特记忆表征的行为模式分离）非常重要（Escherberger和Gage，2014）。然而，背景学习后增加的成人神经发生加速了遗忘（Ackers等人，2014年），强调了限制神经发生的重要性。 几十年前发现的电压门控钾通道Kv1.1（Tempel，Jan和Jan，1988）不仅在成年期表达，而且在胚胎发生期也表达（Hallows和Tempel，1998）。我们对Kv1.1无效突变或Kv1.1的大头畸形移码突变杂合的小鼠进行了双标记镶嵌分析（MADM）研究，以通过Nestin-cre在这些无突变小鼠的少数神经祖细胞中诱导体细胞重组，并表明神经祖细胞及其后代神经元中Kv1.1功能的丧失导致CA 1和齿状回（DG）中神经元的过度产生。海马体（Yang等人，2012年）。我们意想不到的发现提高了Kv1.1作为抑制神经发生的制动器的可能性。 为了研究Kv1.1在胚胎神经发生和成体神经发生中的作用，目的1将评估Kv1.1功能是否在调节神经祖细胞的增殖和/或它们产生的神经元的存活和成熟中重要，并确定Kv1.1的缺失是否导致胚胎发生期间神经祖细胞数量的增加，而目标2将确定Kv1.1功能的丧失如何影响成体神经祖细胞的数量和增殖，以及它们的后代神经元的存活和成熟。最后，在目标3中，我们将研究Kv1.1抑制海马神经元产生的可能机制的几种假设。 发现离子通道对神经发生的内源性抑制并阐明其潜在机制将为如何实现适当平衡的神经发生提供新的见解。此外，海马神经发生的Kv1.1调制的机制和调节的调查有可能确定新的治疗神经退行性疾病和神经精神疾病的目标。

 DESCRIPTION (provided by applicant): Neurogenesis is important for the generation of the nervous system during embryogenesis and also for facilitating the adult hippocampal circuit plasticity involving behavioral pattern separation that transforms similar experiences into distinc memory representations (Jessberger and Gage, 2014). However, increasing adult neurogenesis after contextual learning accelerates forgetting (Ackers et al., 2014), underscoring the importance of restrained neurogenesis. The voltage-gated potassium channel Kv1.1 identified decades earlier (Tempel, Jan and Jan, 1988) is expressed not only in adulthood but also in embryogenesis (Hallows and Tempel, 1998). We conducted Mosaic Analysis with Double Markers (MADM) studies of mice heterozygous for either the Kv1.1 null mutation or the megencephaly frame shift mutation of Kv1.1 to induce somatic recombination via Nestin-cre in a few percent of neural progenitors in these seizure-free mice, and showed that loss of Kv1.1 function in neural progenitors and their progeny neurons causes an overproduction of neurons in both CA1 and the dentate gyrus (DG) of hippocampus (Yang et al., 2012). Our unexpected findings raise the possibility that Kv1.1 acts as a brake for restrained neurogenesis. To examine the role of Kv1.1 in embryonic neurogenesis and adult neurogenesis, Aim 1 will assess whether Kv1.1 function is important in regulating the proliferation of neural progenitors and/or the survival and maturation of the neurons they produce, and determine whether loss of Kv1.1 causes an increase in the number of neural progenitors during embryogenesis, while Aim 2 will determine how the loss of Kv1.1 function affects the number and proliferation of adult neural progenitors, and the survival and maturation of their progeny neurons. Finally, in Aim 3 we will examine several hypotheses for possible mechanisms underlying the action of Kv1.1 to restrain neuron production in the hippocampus. Discovery of endogenous restraint of neurogenesis by ion channels and elucidation of the underlying mechanisms will provide insight regarding how to achieve properly balanced neurogenesis. In addition, investigation of the mechanism and regulation of Kv1.1 modulation of hippocampal neurogenesis has the potential of identifying novel targets for the treatment of neurodegeneration and neuropsychiatric diseases.