Development of Synaptic Plasticity in Visual Cortex

描述（由申请人提供）：大脑皮层中的突触在整个生命过程中会经历其效率的动态变化。特别是，初级视觉皮层的神经元可以利用这种突触可塑性对视觉处理的各个方面进行并行计算。这种突触信号的活动依赖性变化被认为有助于视觉感知、认知表现、技能学习、功能性视觉皮质突触网络的发育重组和完善以及损伤后的适应性反应。在出生后的发育过程中，这些形式的可塑性在其稳健性、内在和外在因素的调节以及潜在的分子过程中经历了巨大的变化。然而，这些形式的功能性突触可塑性的发育调控受到的关注较少。我们利用新皮质突触可塑性的实验模型，该模型基于突触输入与突触后神经元激活的一系列相关性，来表征通常导致长期突触增强（LTP）的初始细胞内钙触发事件。有趣的是，在新生儿视觉皮层中，当相同的序列相关性应用于同一类别的神经元（第2/3层锥体神经元）时，发生的突触可塑性（LTP或长期突触抑制- LTD）在单个细胞之间有所不同。包括NMDA受体、代谢性谷氨酸受体、肌苷三磷酸受体（IPaRs）、ryanodine受体和电压激活钙通道在内的多种钙来源都参与了这些新生儿视觉皮质神经元的这一过程。新生儿皮质LTP或LTD的结果是由细胞内树突状钙瞬态的动力学剖面预测的，该动力学剖面发生在个体相关性和扩散到细胞体的累积钙波的动力学过程中。该方案提供了一个独特的窗口，以了解在出生后发育过程中决定视觉皮层突触变化极性的初始潜在钙信号过程，并提供了一个新的具有挑战性的观点，即第一个钙信号的动力学和振幅如何在随后的下游可塑性激活中至关重要。该项目还首次全面分析了单个第4层和第2/3层神经元之间的单一突触连接，通过突触偶联对的双补丁记录，分析了这些连接的可塑性和钙信号。我们确定了内在细胞差异、成熟度、先前经验（元可塑性）和钙源对信号传导和可塑性过程的影响。

DESCRIPTION (provided by applicant): Synapses in the cerebral cortex undergo dynamic alterations in their efficiency throughout life. In particular, the neurons of the primary visual cortex can use such synaptic plasticity to perform parallel computations on aspects of visual processing. Such activity-dependent changes in synaptic signaling have been suggested to contribute to visual perception, cognitive performance, skill-learning, developmental re-organization and refinement of functional visual cortical synaptic networks and adaptive responses after injury. These forms of plasticity undergo dramatic changes in their robustness, modulation by intrinsic and extrinsic factors and underlying molecular processes during postnatal development. However, the developmental regulation of these forms of functional synaptic plasticity has received less attention. We utilize an experimental model of neocortical synaptic plasticity that is based on serial correlations of synaptic input with activation of the postsynaptic neuron to characterize the initial intracellular calcium triggering events that generally lead to long term synaptic potentiation (LTP). Interestingly, in the neonatal visual cortex, when the identical serial correlations are applied to neurons of the same class (layer 2/3 pyramidal neurons), the synaptic plasticity that occurs (LTP or long term synaptic depression - LTD) varies between individual cells. A variety of sources of calcium including NMDA receptors, metabotropic glutamate receptors, inositide trisphosphate receptors (IPaRs), ryanodine receptors and voltage activated calcium channels all contribute to this process in these neonatal visual cortical neurons. The outcome of LTP or LTD in the neonatal cortex is predicted by the intracellular dendritic calcium transient's kinetic profile that occurs during the individual correlations and the kinetics of the cumulative calcium wave that spreads to the cell body. This protocol offers a unique window into the initial underlying calcium signaling processes that determines polarity of synaptic changes in the visual cortex during postnatal development and provides a new provocative view of how kinetics and amplitude of the very first calcium signals may be critical in the subsequent downstream activation of plasticity. This project also provides the first comprehensive analysis of unitary synaptic connections between individual layer 4 and layer 2/3 neurons with dual patch recording from synaptically coupled pairs with analysis of plasticity and calcium signaling at those connections. We determine the effects of intrinsic cellular differences, maturation, previous experience (metaplasticity) and calcium sources on the signaling and plasticity processes.