Synaptic Plasticity In The Adult And Developing NS

对于神经科学家和整个社会来说，一个关键问题涉及到遗传和环境在人脑出生后发育中的相对作用。环境刺激的范围很广，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的发育计划，正如其基因组所指示的那样。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)如何长期变化以响应神经元活动，2)出生后早期发育期间的突触可塑性与成人的可塑性有何不同，以及3)经验如何通过在发育过程中消除突触来塑造大脑电路。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)。在这些制剂中，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，它似乎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-磷酸受体可以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。结合上面列出的研究目标，这项工作应该会让我们更好地理解环境因素如何在大脑发育中发挥作用，以便我们

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