丁香园论坛专题讨论
默克密理博官方微博东京大学医学院Haruhiko Bito副教授
Department of Neurochemistry
University of Tokyo Graduate School of Medicine
A fundamental question in neuroscience is to understand how an ensemble behavior of 10~100 billion neurons can possibly give rise to a coherent and integrated “brain” that controls the whole human organism for a period of more than eighty years. Our central nervous system is physically hardwired and organized based on evolutionary and developmental principles that are primarily encoded into the genome and that are highly conserved in mammals from rodents to primates. This neural network, however, is able to flexibly recognize and memorize external and internal events as they occur. Furthermore, it can successfully extract patterns and rules from these events, and consciously associate them with abstract meaning and affective values.
As a biochemist, I am particularly fascinated by the molecular basis that governs neuronal cell signaling that regulates plasticity within a hardwired circuit. Since Cajal's 'Neuron Doctrine', the critical importance of both cellwide and synapse-specific signaling has been recognized. Yet, tangible experiments to test hypotheses became available only in the last 15 years or so.
To decipher the signal transduction machinery that enables specific patterns of synaptic inputs to control the cellwide transcriptional output of hippocampal neurons, we have systematically investigated the molecular basis of the signaling from synapses to the nucleus during synaptic plasticity. We thus uncovered an activity-dependent protein kinase cascade CaMKK-CaMKIV that critically controls the amplitude and time course of phosphorylation of a nuclear transcription factor CREB downstream of synaptic activity, thereby activating a plethora of adaptive transcriptional responses within a neuronal circuit. We further identified a potent synaptic activity-responsive element (SARE) on the promoter of one of the most prominent neuronal activity-induced genes, namely Arc/Arg3.1. Strikingly, the SARE of Arc gene consisted of a unique cluster of binding sites for CREB, MEF2 and SRF/TCF, each of which significantly contributing to converting synaptic responses into a transcriptional one..
Current efforts are being focused to take advantage of the precise understanding of these mechanistic details to visualize and manipulate the behavior of specific neuronal circuits in which the signaling from synapses to the nucleus has been enhanced. These experiments will help further dissect the intricate and interactive relationship between the information encoded into the genome and the ongoing synaptic activity in our brain.
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