Synaptic basis for map plasticity in cerebral cortex

感觉经验有力地调节大脑皮层回路的发育，有助于皮层发育的后期阶段。经验改变皮层回路的细胞机制尚不清楚。这一过程可以在大脑皮层的感觉区域中进行研究，这些区域包含有序的感觉地图，其地形会被感觉经验改变。标准模型假定，地图可塑性的快速组件反映了长期突触增强（LTP）和抑郁症（LTD），由N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体介导，在特定的皮层兴奋性突触。最近的证据支持这一模型，直接检测LTP和LTD在皮层突触诱导的感觉经验。然而，新的研究结果表明，在早期的关键时期，LTD在许多皮层突触不通过经典的NMDA依赖性机制运作，而是通过新发现的内源性大麻素系统和大麻素（CB）受体参与逆行信号传导。皮质中CB依赖性LTD的细胞信号传导途径尚不清楚。我们建议阐明这些机制在啮齿动物的躯体感觉皮层的胡须区。我们还将测试是否如这些发现所示，CB受体在皮层回路的发育和可塑性中发挥意想不到的因果作用。 这些实验将扩展目前的经验依赖性皮质发育模型，超越NMDA依赖性LTP和LTD，包括大麻素依赖性机制。研究结果可能为可塑性相关的神经系统疾病（包括精神发育迟滞、自闭症和学习障碍）提供新的治疗策略。皮质发育中大麻素信号通路的参与也可能对儿童和胎儿发育期间大麻素滥用产生重大影响。

Sensory experience powerfully regulates the development of circuits in the cerebral cortex, contributing to late stages of cortical development. The cellular mechanisms by which experience alters cortical circuits are not yet understood. This process can be studied in sensory areas of cerebral cortex, which contain orderly sensory maps whose topography is altered by sensory experience. The standard model posits that rapid components of map plasticity reflect long-term synaptic potentiation (LTP) and depression (LTD), mediated by N-methyl-D-aspartate (NMDA)-type glutamate receptors, at specific cortical excitatory synapses. Recent evidence has supported this model by directly detecting LTP and LTD induced at cortical synapses by sensory experience. However, new findings suggest that during early critical periods, LTD at many cortical synapses does not operate by classical, NMDA-dependent mechanisms, but instead involves retrograde signaling via the newly discovered endocannabinoid system and cannabinoid (CB) receptors. The cellular signaling pathways for CB-dependent LTD in cortex are not understood. We propose to elucidate these mechanisms in the whisker region of rodent somatosensory cortex. We will also test whether, as these findings suggest, CB receptors play an unexpected causal role in development and plasticity of cortical circuits. These experiments will expand current models of experience-dependent cortical development beyond NMDA-dependent LTP and LTD, to include cannabinoid-dependent mechanisms. Results may suggest novel therapeutic strategies for plasticity-related neurological disorders, including mental retardation, autism, and learning disability. Involvement of cannabinoid signaling pathways in cortical development may also have major implications for cannabinoid abuse in children and during fetal development.