Nogo-A Modulates the Synaptic Excitation of Hippocampal Neurons in a Ca2+-Dependent Manner

Metzdorf, Kristin; Fricke, Steffen; Balia, Maria Teresa; Korte, Martin; Zagrebelsky, Marta

doi:10.3390/cells10092299

Article / Chapter Fri Sep 3 2021 CC BY 4.0

Published

Nogo-A Modulates the Synaptic Excitation of Hippocampal Neurons in a Ca²⁺-Dependent Manner

Metzdorf, Kristin ; Fricke, Steffen ; Balia, Maria Teresa ; Korte, Martin ; Zagrebelsky, Marta

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABA_ARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca²⁺-permeable GluA2-lacking AMPARs and increased intracellular Ca²⁺ levels due to a higher Ca²⁺ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.