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

ABSTRACT: 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.

SUBMITTER: Metzdorf K

PROVIDER: S-EPMC8467072 | biostudies-literature |

REPOSITORIES: biostudies-literature

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