Synaptic Plasticity In The Adult And Developing NS

对于神经科学家和整个社会来说，一个关键问题是遗传和环境在人类大脑出生后发育中的相对作用。环境刺激范围很广，从有害的（例如化学毒物）到有益的（母亲的指示），但所有这些都有可能影响儿童基因组指导的发育程序。突触和发育可塑性小组的研究重点是确定1）大脑中的连接（突触）如何响应神经元活动而长期变化，2）出生后早期发育期间的突触可塑性如何不同于成人的可塑性，以及3）经验如何通过发育期间的突触消除来塑造脑回路。有证据表明，突触功效的长期变化需要新RNA的表达，为此，我们专注于神经元动作电位对基因转录的调节。已知的一种随着神经元活动而开启的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的细胞核，这些细胞核首先在体外进行电刺激（在切片的情况下）或用药物刺激神经元活动（在神经元培养物的情况下）。在这些制剂中，我们已经确定了一个高分子量的实体反应的抗体对活性ERK，似乎增加神经元刺激后。我们已经进一步确定了这种复合物的推定成分，并假设酶转氨酶，它可以交联蛋白质在钙依赖的方式，是重要的稳定核复合物。这一过程可能是重要的锚定ERK途径的组成部分在核中，以促进或指导转录。在一项相关研究中，我们已经确定阻断N-甲基-D-阿帕沙酸受体通过阻断某些刺激模式诱导的动作电位产生来抑制ERK激活。这些结果确立了动作电位在响应突触活动的ERK激活中的重要性。实验室正在进行的研究旨在了解ERK依赖的转录因子调节神经元活动诱导的基因的调节。这些研究检查神经元活动的转录调控将导致更好地了解突触可塑性所需的基因是如何调节的。连同上面列出的研究目标，这项工作应该使我们更好地了解环境因素如何在大脑发育中发挥作用，

A critical issue for both neuroscientists and society at large concerns the relative roles of genetics and environment in the postnatal development of the human brain. Environmental stimuli are wide ranging, from the detrimental (chemical toxicants, for example) to the beneficial (a mother's instructions), but all have the potential to influence the developmental program of a child as directed by its genome. The research done in the Synaptic and Developmental Plasticity Group focuses on determining 1) how the connections in the brain (synapses) change on a long-term basis in response to neuronal activity, 2) how synaptic plasticity during early postnatal development is different from plasticity in the adult, and 3) how experience shapes brain circuitry through synapse elimination during development. 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 appears to 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-apsartate 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. Together with the research goals listed above, this work should bring us a better appreciation of how environmental factors play a role in brain development so that we