Role of Nogo-A in regulating synaptic transmission in the hippocampus – The involvement of inhibition

Abstract

Learning and memory processes shape the function and structure in the brain. The precise temporal modulation of the synaptic connections in the neuronal network is important to regulate their function. While it is necessary that synapses are plastic in order to enable the acquisition and implementation of new information, the stabilization of synapses is crucial to allow long-term storage and recall of these data. A set of molecules has been described to modify this delicate balance between plastic changes and stabilization. In this study, the role of one of these molecules, namely Nogo-A, in regulating the interplay between plasticity and stability was investigated. Nogo-A has been shown to limit functional and structural recovery after an injury in the adult central nervous system (CNS) and has recently been implicated as a suppressor of activity-dependent synaptic plasticity as well as learning and memory processes. However, the underlying mechanisms of how Nogo-A modulates synaptic function and especially its acute actions on synaptic transmission remained unknown. This work shows via patch clamp electrophysiology that Nogo-A bidirectionally regulates neuronal transmission on a fast time scale. While Nogo-A loss-of-function resulted in an increase in excitatory synaptic transmission within few minutes, inhibitory synaptic transmission was decreased simultaneously. Moreover, quantum dot-based single particle tracking paired with calcium imaging revealed that the lateral diffusion of GABAA receptors at synaptic and extrasynaptic sites as well as the concentration of intracellular calcium in dendrites was simultaneously increased within few minutes of Nogo-A loss-of-function. Furthermore, Nogo-A was found to limit the number and length of dendritic spines of CA3 hippocampal neurons in an activity-dependent manner as demonstrated via live cell imaging. Finally, spatial learning of mice in the Morris water maze and paired immunohistochemistry showed that Nogo-A seems not to control the activity of parvalbumin-positive inhibitory neuron networks to control spatial learning. Taken together, this study reveals a new mechanism by which Nogo-A modulates neuronal transmission on a fast time scale and contributes to the understanding of how Nogo-A stabilizes neuronal circuits, which has its price, it limits plasticity in the mature brain.