Synaptic retinoic acid signaling and homeostatic synaptic plasticity

Abstract

One of the defining features of the nervous system is its ability to modify synaptic strength in an experience-dependent manner. Chronic elevation or reduction of network activity activates compensatory mechanisms that modulate synaptic strength in the opposite direction (i.e. reduced network activity leads to increased synaptic strength), a process called homeostatic synaptic plasticity. Among the many mechanisms that mediate homeostatic synaptic plasticity, retinoic acid (RA) has emerged as a novel signaling molecule that is critically involved in homeostatic synaptic plasticity induced by blockade of synaptic activity. In neurons, silencing of synaptic transmission triggers RA synthesis. RA then acts at synapses by a non-genomic mechanism that is independent of its well-known function as a transcriptional regulator, but operates through direct activation of protein translation in neuronal dendrites. Protein synthesis is activated by RA-binding to its receptor RARα, which functions locally in dendrites in a non-canonical manner as an RNA-binding protein that mediate RA’s effect on translation. The present review will discuss recent progress in our understanding of the novel role of RA, which led to the identification of RA as a critical synaptic signaling molecule that mediates activity-dependent regulation of protein synthesis in neuronal dendrites. This article is part of a Special Issue entitled ‘Homeostatic Plasticity’.

Rapid Suppression of Inhibitory Synaptic Transmission by Retinoic Acid

“…At 1 DIV, CA1 of slices from RAR␣ floxed mice were injected with lentiviral vectors expressing CRE recombinase or a truncated and inactive version of Cre (⌬Cre), gifts from Dr. Thomas Südhof's laboratory (Stanford University, Stanford, CA; Kaeser et al, 2011), together with different rescue truncated versions of RAR␣. Lentivirus was produced and purified as described previously (Aoto et al, 2008;Sarti et al, 2012). Pharmacological manipulations of cultured hippocampal slices include the following: RA (2 M, 4 h) and TTX ϩ CNQX (2 M ϩ 20 M, 36 h).…”

“…The effect of RA on excitatory synaptic transmission is mediated by a novel mechanism that does not require transcriptional regulation but operates through translational derepression of mRNAs that are bound to RAR␣ (Aoto et al, 2008;Poon and Chen, 2008;Sarti et al, 2012). We asked whether the action of RA on inhibitory synaptic transmission uses a similar nongenomic mechanism.…”

“…The RA receptor RAR␣ is required for RA's effect on synaptic excitation because both shRNA-mediate knockdown and Crerecombinase-mediated conditional knock RAR␣ eliminated RA's action on excitatory synaptic transmission and blocked homeostatic upregulation of synaptic excitation (Aoto et al, 2008;Sarti et al, 2012). To investigate the requirement for RAR␣ in downscaling of synaptic inhibition, we infected CA1 pyramidal neurons from conditional RAR␣ KO mice (RAR␣ fl/fl ) with lentivirus expressing either an active or inactive GFP-tagged Crerecombinase (Cre or ⌬Cre) (Kaeser et al, 2011).…”

“…Several molecular pathways are known to participate in the homeostatic upregulation of excitatory synaptic strength after prolonged reduction of excitatory synaptic transmission (Yu and Goda, 2009;Turrigiano, 2012;Chen et al, 2013). Recent findings show that long-lasting changes in activity also modulate inhibitory transmission in the same cells or systems that express homeostatic changes at excitatory synapses (Kilman et al, 2002;Saliba et al, 2009).…”

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

“…Homeostatic synaptic plasticity is a type of compensatory mechanism activated during chronic elevation or reduction of network activity to modulate synaptic strength in the opposite direction (for example, reduced network activity leads to increased synaptic strength) (1,2). Retinoic acid (RA) is a key signaling molecule in a form of homeostatic synaptic plasticity induced by reduced excitatory synaptic activity (3)(4)(5). Prolonged inhibition of excitatory synaptic transmission leads to a compensatory increase in synaptic excitation and a decrease in synaptic inhibition (4,5).…”