Functional consequences of kainate receptor stimulation during neonatal development

在所有哺乳动物中，围产期(即出生前后)大脑发育是一个复杂和高度动态的时期，包括大鼠和人类。特别是在人类妊娠晚期，但在大鼠出生后的前3周，大脑生长迅速，这是大脑化学和神经元之间形成的连接发生巨大变化的时期，这将最终决定大脑功能。大脑生长激增的复杂性也使其成为发育中有机体的脆弱性窗口，在这种情况下，看似轻微的创伤或化学毒性可能会导致发育异常，后来表现为神经疾病。社会上许多最重要的神经疾病往往源于神经发育，包括癫痫、脑瘫、自闭症和精神分裂症。精神分裂症是一种精神病学诊断，描述了一种通常以对现实的感知或表达障碍为特征的精神疾病，通常是在严重的社会功能障碍的背景下。许多人认为，对发育中的神经系统的损害可能会潜伏到成熟，然后表现为精神分裂症的症状。了解疾病和开发新的治疗方法需要模拟临床疾病的起源和最终表现的动物模型。因此，可以检验假说的新模型的开发和表征可以为人类神经病理疾病的机制提供洞察力。我们之前已经证明，在大脑发育的关键时期，兴奋性传递的早期变化会产生持久的变化，这些变化提示精神分裂症表现出的一些症状。拟议的实验的重点是更好地表征这些变化与精神分裂症的相关性。这些研究的结果将更好地理解围产期谷氨酸能信号的变化与与精神分裂症和其他神经疾病相关的神经行为和大脑回路的持久变化之间的关系。

Perinatal (i.e. around the time of birth) brain development is a complex and highly dynamic period in all mammals, including rats and humans. The brain growth spurt in particular, which occurs in late 3rd trimester in humans but in the first 3 postnatal weeks in rats, is a time of massive changes in brain chemistry and in the connections formed between neurons, that will ultimately determine brain function. The complexity of the brain growth spurt also makes it a window of vulnerability for the developing organism, in which seemingly minor trauma or chemical toxicity can result in developmental abnormalities that later manifest in neurological disease. Many of society's most important neurological disorders are often neurodevelopmental in origin, including epilepsy, cerebral palsy, autism, and schizophrenia. Schizophrenia is a psychiatric diagnosis that describes a mental illness generally characterized by impairments in the perception or expression of reality, often in the context of significant social dysfunction. Many believe that damages to the developing nervous system may lay dormant until maturity and then be expressed in the symptoms of schizophrenia. Understanding disease and developing new therapies requires animal models that mimic the origins and the ultimate presentation of the clinical condition. Thus, development and characterization of new models in which hypotheses can be tested can provide insight into mechanisms of human neuropathological diseases. We have previously shown that early alterations in excitatory transmission, during critical periods of brain development, produce lasting changes which are suggestive of some of the symptoms manifested in schizophrenia. The focus of the proposed experiments is to better characterize these changes with respect to their relevance to schizophrenia. Results from these studies will offer a better understanding of the relationship between changes in perinatal glutamatergic signaling and lasting alterations in neurobehaviour and brain circuitry relevant to schizophrenia and other neurological diseases.