Experience-dependent plasticity of synaptic structure.-Resubmission-1

 描述(申请人提供)：本提案的目的是阐明树突状钙离子刺激物在小鼠大脑皮质学习依赖型突触可塑性中的作用。树突状钙尖峰通过放大同步激活的兴奋性突触输入来增强单个神经元的计算能力。体外研究表明，树突状钙峰在活性依赖性突触增强和抑制中起重要作用。树突状钙离子刺激物在突触可塑性中的体内功能仍不清楚。我们的初步研究表明，不同的运动学习任务在小鼠初级运动皮质的V(L5)层锥体神经元的不同顶束分支上诱导树突状钙峰。我们建议研究这种任务和分支特异的树突钙离子尖峰如何影响运动皮质突触可塑性的诱导和维持。结合体内双光子成像和神经元活性的药物遗传学操作等实验方法，我们将确定树突状钙峰如何在不同的运动学习任务中引起单个L5锥体神经元不同顶支的突触增强和去增强。我们还将研究树突状钙离子尖峰是否促进新树突棘的分支特异性形成，以及新形成的脊椎是否以任务特定的方式与相邻的脊椎协同活动。我们的初步研究表明，表达生长抑素的中间神经元的失活扰乱了分支特异性钙尖峰的产生。我们将进一步研究这种干扰是否会影响运动学习过程中突触可塑性的诱导和维持。此外，我们将研究在脆性X综合征小鼠模型中，表达生长抑素的中间神经元的活性、分支特异性钙尖峰的产生和树突棘的可塑性是如何改变的。拟议的实验将揭示树枝特异的树突钙峰在学习和记忆形成过程中诱导和维持突触可塑性的基本作用。这些研究还将为开发治疗智力残疾和自闭症的新策略提供新的见解。

 DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the role of dendritic Ca2+ spikes in learning-dependent synaptic plasticity in the mouse cortex. Dendritic Ca2+ spikes enhance the computational power of individual neurons by amplifying synchronously activated excitatory synaptic inputs. In vitro studies have shown that dendritic Ca2+ spikes play an important role in activity-dependent synaptic potentiation and depression. The in vivo function of dendritic Ca2+ spikes in synaptic plasticity remains elusive. Our preliminary studies show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of layer V (L5) pyramidal neurons in the mouse primary motor cortex. We propose to investigate how such task-and branch-specific dendritic Ca2+ spikes affect the induction and maintenance of synaptic plasticity in the motor cortex. With a combination of experimental approaches including in vivo two-photon imaging and pharmacogenetic manipulations of neuronal activity, we will determine how dendritic Ca2+ spikes cause synaptic potentiation and depotentiation on different apical branches of individual L5 pyramidal neurons in response to different motor learning tasks. We will also investigate whether dendritic Ca2+ spikes promote branch-specific formation of new dendritic spines and whether newly-formed spines are co-active with adjacent spines in a task-specific manner. Our preliminary studies indicate that inactivation of somatostatin-expressing interneurons disrupts branch-specific generation of Ca2+ spikes. We will further investigate if such disruption affects the induction and maintenance of synaptic plasticity during motor learning. In addition, we will examine how the activity of somatostatin- expressing interneurons, the generation of branch-specific Ca2+ spikes and dendritic spine plasticity are altered in a mouse model of Fragile X syndrome. The proposed experiments will reveal the fundamental role of branch-specific dendritic Ca2+ spikes in the induction and maintenance of synaptic plasticity during learning and memory formation. These studies will also provide novel insights into developing new strategies for the treatment of intellectual disability and autism.