Selective disruption of hippocampal dentate granule cells in autism: impact of PT

描述(申请人提供)：在孩子的发育过程中，大部分脑细胞是在出生前产生的。然而，有一组脑细胞是在婴儿时期大量产生的。这发生在大脑中一个叫做海马体的区域。这些细胞对记忆、认知和语言的正常发展很重要，而这些细胞的破坏在自闭症儿童中存在。这些细胞的破坏也可能导致自闭症儿童癫痫的流行。虽然这些细胞负责自闭症的关键特征是有道理的，但患有自闭症的儿童在大脑的许多其他部分也表现出变化。不幸的是，我们对哪些变革是重要的认识有限，减缓了这一领域的进展。因此，在目前的提案中，我们将研究消除一种已知与自闭症有关的基因对这些后期生成细胞的影响。这些研究将揭示选择性地破坏这些细胞是否可以重现自闭症的特征。证明这些细胞在自闭症(或癫痫等相关疾病)的发展中发挥重要作用，将为开发保护这些脆弱细胞的新疗法提供令人信服的理论基础。此外，由于这些细胞是在发育很晚的时候出生的，实际上是从童年到成年产生的，因此有可能防止自闭症诊断后出生的细胞受到破坏，从而允许大脑自然恢复自身。我们希望这些研究将推动我们更接近开发新的、更有效的自闭症治疗方法。与公共卫生相关：拟议的研究试图通过确定选择性破坏晚期生成的神经元-特别是海马齿状颗粒细胞-是否有助于自闭症的关键特征，从而更好地阐明自闭症的原因。这将通过一种新型的转基因小鼠组合来实现，有选择地从这些晚生成的神经元中消除与自闭症有关的基因。值得注意的是，尽管在大多数情况下，自闭症的近端原因仍有待确定，但这些神经元的晚一代(在胚胎晚期和婴儿期)可能使它们特别容易受到新生儿面临的各种侮辱(例如感染)的影响。该提案还将研究颗粒细胞在癫痫发展中的作用，癫痫是一种与自闭症最常见的疾病。

DESCRIPTION (provided by applicant): During the development of a child, most brain cells are generated before birth. There is one group of brain cells, however, that are generated in large numbers in infancy. This occurs in a brain region called the hippocampus. These cells are important for the normal development of memory, cognition and language, and disruption of these cells is present in children with autism. Disruption of these cells may also contribute to the prevalence of epilepsy in children with autism. Although it makes sense that these cells are responsible for key features of autism, children with the disease exhibit changes in many other parts of the brain as well. Our limited understanding of which changes are important, unfortunately, has slowed progress in the field. In the present proposal, therefore, we will examine the impact of eliminating a gene known to be involved in autism on these late-generated cells. These studies will reveal whether selectively disrupting these cells can reproduce features of autism. Demonstrating that these cells play an important role in the development of autism (or associated conditions like epilepsy), will provide a compelling rationale to develop new therapies to protect these vulnerable cells. In addition, since these cells are born so late in development, and are actually produced through childhood and into adulthood, it may be possible to prevent the disruption of cells born after a diagnosis of autism and thus allow the brain to naturally restore itself. It is our hope that these studies will move us closer to developing new and more effective treatments for autism. PUBLIC HEALTH RELEVANCE: The proposed studies seek to better elucidate the causes of autism by determining whether selective disruption of late-generated neurons - specifically hippocampal dentate granule cells - contributes to key features of autism. This will be achieved using a novel combination of transgenic mice to selectively eliminate a gene implicated in autism from these late-generated neurons. Significantly, although the proximal cause of autism remains to be determined in most cases, the late generation of these neurons (in the late embryonic period and in infancy) may make them uniquely vulnerable to a variety of insults faced by the newborn child (e.g. infection). The proposal will also examine the role of granule cells in the development of epilepsy, the condition most commonly associated with autism.