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 GABAARs 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.
Highlights
A tight balance between excitatory and inhibitory synaptic transmission lies beneath brain function from the developmental stage throughout life
Nogo-A signaling promotes inhibitory signaling by regulating the synaptic localization of γ-aminobutyric acid type A receptors (GABAA Rs; [23]) to strengthen inhibitory synaptic transmission
We recently showed, in two separate series of experiments that Nogo-A signaling regulates the recruitment of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and the confinement of GABAA Rs, respectively, at synaptic sites [23]
Summary
A tight balance between excitatory and inhibitory synaptic transmission lies beneath brain function from the developmental stage throughout life. The regulation of experience-dependent synaptic plasticity at the onset of the critical period takes place through changes in the GABA-mediated transmission, by these means establishing an adaptive E/I balance [2,3]. The strength of inhibitory synaptic transmission depends on the number of gamma-aminobutyric acid receptors (GABAA Rs) present at synapses [5]. The synaptic localization of GABAA Rs is, in turn determined both by their clustering via synaptic scaffold proteins as well as by the control of their lateral diffusion through changes in the intracellular Ca2+ concentration [6]. The number of GABAA Rs accumulating at the synapse has been shown to depend on the release of Ca2+ from the internal stores via activation of the IP3R1 and PKC [7,8]. GABAA R diffusion has been shown to rely upon the Ca2+ influx via NMDA receptors followed by the downstream activation of the phosphatase calcineurin and the subsequent dephosphorylation at the Serine-327 of the GABAA R γ2 subunit [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
