PMC

A model for RA-mediated regulation of synaptic strength. (A) Normal excitatory synaptic transmission maintains dendritic calcium levels above a critical threshold, which, through an unknown mechanism, inhibits RA synthesis. (B) During synaptic inactivity (➀), reduced dendritic calcium levels enable RA synthesis (➁). Binding of RA to RARα de-represses mRNA translation and allows dendritic protein synthesis to occur locally (➂). Newly synthesized calcium-permeable homomeric AMPA receptors are inserted into local synapses (➃), leads to increased excitatory synaptic strength.

FMRP and RARα are present in neuronal RNA granules. (A) Left: A cartoon showing location of RNA granules in neurons. Right: FMRP, labeled by 5 nm gold particles (arrowheads), is enriched in dendritic RNA granules. (B) Double immunogold labeling of FMRP (arrowheads) and GluA1 in dendritic RNA granules of cultured hippocampal neurons. Ten-minute treatment of 1 μM RA, but not DMSO rapidly increased GluA1 protein synthesis in RNA granules. (C) RA stimulation increased RARα (arrows) accumulation in RNA granules within 5 min of treatment. (D) RARα (arrowheads) is found enriched in RNA granules actively translating GluA1 (arrows). All scale bars: 200 nm. Adapted from .

Global and local mechanisms for homeostatic synaptic plasticity. Global HSP is triggered by a reduction in neuronal firing that leads to a drop in somatic calcium level. This decreases the amount of activated CaMKIV in the nucleus, which leads to increased transcription of “scaling factors”, and enhanced accumulation of heteromeric AMPA receptors globally at all excitatory synapses. The increased excitatory synaptic strength thus restores neuronal firing rate back to normal. Local HSP is triggered by a drop in dendritic calcium levels due to reduced excitatory synaptic transmission in a subset of synapses. Reduced calcium levels in dendrites dis-inhibit RA synthesis. RA enhances local protein synthesis and synaptic insertion of homomeric AMPA receptors locally in dendrites (depicted by the orange circle), thus restores dendritic calcium levels back to normal.