Stabilizers and negative modulators of synaptic transmission and plasticity: the Nogo-A signaling system

大脑进行学习和记忆过程的能力依赖于兴奋性和抑制性突触传递之间的严格调控平衡。在参与调节中枢神经系统兴奋/抑制平衡的分子中，髓鞘相关的神经突起生长抑制因子Nogo-A尤其令人感兴趣。事实上，我们在前一个资助时期的工作表明，Nogo-A信号通过其受体S1PR2和NgR1分别通过控制AMPA和GABAA受体的突触定位，在快速的时间尺度上相互调节兴奋性和抑制性突触传递的强度。特别是，Nogo-A功能的丧失导致兴奋的加强和抑制的减弱。这些结果和我们的初步数据表明，Nogo-A调节神经元的兴奋性。这在细胞和分子机制的背景下很有趣，该机制调节新记忆的编码，特别是每个神经元被分配到特定记忆痕迹的概率。事实上，虽然特定脑区的所有主要神经元在记忆编码过程中都被激活，但在基于神经元兴奋性水平的竞争过程中，只有一小部分被招募到任何记忆中。有趣的是，我们和其他人已经展示了Nogo-A信号调节依赖活动的突触可塑性以及学习和记忆过程。在这个项目中，我们计划研究Nogo-A信号调节E/I平衡的细胞和分子机制以及行为后果。我们将结合电生理、成像和行为方法来评估Nogo-A信号是否通过其受体通过控制海马体和杏仁核编码过程中的神经元分配来调节记忆过程(即空间记忆和上下文相关的恐惧条件反射)。此外，我们的目的是在创伤后应激障碍模型中利用不同的行为范式来研究Nogo-A在调节神经元兴奋性和记忆分配中的生理病理相关性。这些实验将为调控突触传递和神经元兴奋性的核心机制以及Nogo-A信号在生理和病理生理条件下的行为后果提供见解。

The ability of the brain to perform learning and memory processes depend on a tightly regulated balance between excitatory and inhibitory synaptic transmission. Among the molecules involved in regulating the excitation/inhibition balance of the CNS network, the myelin-associated neurite growth inhibitor Nogo-A is of special interest. Indeed, our work performed during the previous funding period shows that Nogo-A signaling via its receptors S1PR2 and NgR1 reciprocally modulates the strength of excitatory and inhibitory synaptic transmission at a fast time scale by controlling the synaptic localization of AMPA and GABAA receptors, respectively. In particular, loss-of-function for Nogo-A results in the strengthening of excitation paired to the weakening of inhibition. These results, and our preliminary data indicate that Nogo-A regulates neuronal excitability. This is interesting in the context of the cellular and molecular mechanisms regulating the encoding of new memory and specifically the probability of each neuron to be allocated to a particular memory trace. In fact while all principal neurons in a specific brain region are activated during memory encoding, only a small portion of them is recruited into any memory in a competition process based on the levels of neuronal excitability. Interestingly, Nogo-A signalling has been shown, by us and others to modulate activity-dependent synaptic plasticity as well as learning and memory processes.In this project we plan to investigate the cellular and molecular mechanisms and the behavioural consequences of the modulation of the E/I balance by Nogo-A signalling. We will combine electrophysiological, imaging and behavioral methods to assess whether Nogo-A signalling via its receptors regulates memory processes (i.e. spatial memory and context-dependent fear conditioning) by controlling neuronal allocation during encoding in the hippocampus and amygdala. Moreover, we aim at addressing the physio-pathological relevance of Nogo-A in modulating neuronal excitability and memory allocation using different behavioral paradigms in a model of post-traumatic stress disorder.These experiments will provide insights into the core mechanisms regulating synaptic transmission and neuronal excitability as well as into the behavioural consequences of Nogo-A signalling under physiological and pathophysiological conditions.