Mechanisms Of Synaptic Plasticity In The Adult And Devel

环境健康中的一个长期问题是需要了解环境在人脑发育中所起的作用。新生儿的大脑特别容易受到感觉环境的破坏，这可能会对其生理和形态产生深远的影响。发育中的大脑对感官操纵或环境毒物的环境影响的这种敏感性，在出生后生活的特定关键时期尤为明显。一方面，这种敏感性使发育中的大脑特别容易受到有毒侮辱。另一方面，可塑性？神经元或突触之间的连接，对于完善出生后发育过程中的大脑电路至关重要。类似的改变突触的机制很可能是成人学习的基础。因此，我们的主要兴趣在于确定长时间突触可塑性的分子基础。为了了解突触变化如何持续一生，我们研究了神经元活动如何调节基因转录以巩固突触变化。 有证据表明，突触效能的长期变化需要表达新的RNA，为此，我们专注于神经元动作电位对基因转录的调节。已知的与神经元活动有关的一种激酶是细胞外信号调节激酶(ERK)。我们使用从少量脑组织中分离出来的细胞核，这些脑组织首先在体外受到电刺激(对于切片)，或者用药物治疗来刺激神经元活动(对于神经元培养)。在这些准备中，我们已经确定了一种对抗活性ERK抗体起反应的高分子量实体，该实体在神经元刺激后增加。我们进一步鉴定了这个复合体的可能成分，并假设转谷氨酰胺酶在稳定核复合体中起重要作用。转谷氨酰胺酶可以钙依赖的方式使蛋白质交联。这一过程可能在将ERK途径组件锚定在细胞核中以促进或指导转录过程中发挥重要作用。在一项相关的研究中，我们已经证实，阻断N-甲基-D-天冬氨酸受体通过阻断某些刺激模式诱导的动作电位的产生来抑制ERK的激活。这些结果证实了动作电位在ERK激活反应突触活动中的重要性。实验室中正在进行的研究旨在了解依赖ERK的转录因子的调节作用，这些转录因子调节由神经元活动诱导的基因。这些通过神经元活动进行转录调控的研究将有助于更好地理解突触可塑性所需的基因是如何调控的。 我们的长期利益旨在首先确定关键时期形式的突触可塑性发育下调的性质，其次确定神经元活动如何导致突触消除。我们已经开始开发技术，可以用来研究关键时期的活动依赖型突触消除。通过了解发育过程中突触可塑性的分子和细胞机制，我们可能开始了解发育过程中暴露于环境毒物如何对认知和疾病易感性产生终身影响。

A longstanding issue in environmental health is the need to understand the role the environment plays in human brain development. The brain of the neonate is particularly susceptible to disruption of the sensory environment, which can have profound effects on its physiology and morphology. Such susceptibility of the developing brain to environmental influence by sensory manipulation or to environmental toxicants is particularly pronounced during defined critical periods of postnatal life. On the one hand, this susceptibility makes the developing brain particularly vulnerable to toxic insults. On the other hand, the ?plasticity? of the connections between neurons, or synapses, is critical for refining brain circuitry during postnatal development. Similar mechanisms for changing synapses are likely to serve the basis for learning in the adult. Our primary interest, therefore, has been to determine the molecular basis of long-lasting synaptic plasticity. To understand how synaptic changes persist for a lifetime, we study how neuronal activity regulates gene transcription to consolidate synaptic changes. Evidence suggests that the long-term changes in synaptic efficacy require expression of new RNA and toward that end, we have focused on the regulation of gene transcription by neuronal action potentials. One kinase that is known to be turned on with neuronal activity is the Extracellular signal Regulated Kinase (ERK). We use nuclei isolated from small amounts of brain tissue, which had first been electrically stimulated in vitro (in the case of slices) or treated with drugs to stimulate neuronal activity (in the case of neuronal cultures). In these preparations, we have identified a high molecular weight entity reactive to antibodies against active ERK that increases after neuronal stimulation. We have further identified putative components of this complex and hypothesize that the enzyme transglutaminase, which can crosslink proteins in a calcium dependent fashion, is important in stabilizing the nuclear complexes. This process may be important in anchoring ERK pathway components in the nucleus to facilitate or direct transcription. In a related study, we have established that blockade of the N-methyl-D-aspartate receptor inhibits ERK activation by blocking action potential generation induced with certain stimulation patterns. These results establish the importance of action potentials in ERK activation in response to synaptic activity. Ongoing studies in the lab are directed toward understanding ERK-dependent modulation of transcription factors that regulate genes induced with neuronal activity. These studies examining transcriptional regulation by neuronal activity will lead to a better understanding of how genes required for synaptic plasticity are regulated. Our longer term interests are aimed at determining first, the nature of the developmental down-regulation of synaptic plasticity in the form of critical periods, and second, how neuronal activity leads to synapse elimination. We have begun to develop techniques by which activity-dependent synapse elimination during critical periods can be studied. By understanding the molecular and cellular mechanisms of synaptic plasticity during development, we may begin to understand how exposure to environmental toxicants during development can have life-long consequences on cognition and susceptibility to disease.