Retinoic Acid Signaling Mediates Homeostatic Plasticity in Cortex
Material below summarizes the article Retinoic Acid Receptor RARα-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex, published on October 24, 2018, in JNeurosci and authored by Lei R. Zhong, Xin Chen, Esther Park, Thomas C. Südhof, and Lu Chen.
The ability of an individual to fully function — to think, feel, plan, and act — depends on the synaptic connections formed between neurons in the brain.
The process through which synaptic connections change with experience is referred to as synaptic plasticity. Defective synaptic plasticity has been implicated in various neurological diseases, so a major effort in neuroscience research is to study molecular and cellular mechanisms underlying synaptic plasticity.
Most current research focuses on Hebbian plasticity, a form of synaptic plasticity believed to directly underlie our ability to learn and form memories. Coordinated activity between pre-synaptic and post-synaptic neurons drives strengthening of the connection, while out-of-sync activity leads to weakening of the connection.
However, the self-reinforcing nature of Hebbian plasticity, without any corrective mechanisms, leads to imbalanced synaptic activity and network instability. For example, LTP leads to synaptic strengthening and more correlated pre- and post-synaptic activity, which could facilitate additional LTP and promotes runaway plasticity.
Our research focuses on a form of non-Hebbian plasticity, called homeostatic plasticity, that acts as the major neural mechanism to counter the runaway tendency of Hebbian plasticity by providing compensatory changes in cell excitability or synaptic strength to keep network activity in check.
We have previously established with in vitro preparations that retinoic acid (RA), a metabolite of vitamin A, and its receptor RARα are key molecules mediating homeostatic synaptic plasticity at both excitatory and inhibitory synapses. However, whether synaptic RA signaling is essential for homeostatic synaptic plasticity in an intact circuit in vivo remained unclear.
To answer this question, we examined synaptic inputs onto pyramidal neurons in Layer 2/3 of mouse primary visual cortex (V1), where robust visual experience-induced homeostatic synaptic plasticity has been established.
We first examined the effect of direct RA signaling activation in acute visual cortical slices by exogenous RA. We found synaptic inhibition, but not excitation, was selectively affected in juvenile mice — miniature inhibitory post-synaptic currents (mIPSCs) onto L2/3 pyramidal neurons were largely reduced in amplitude and frequency after retinoic acid exposure.
Our previous work showed synaptic RA signaling is mediated by RARα. IPSCs in pyramidal neurons are generated by their connected inhibitory interneurons. To tease apart the relative contribution of RARα expressed in presynaptic inhibitory interneurons and postsynaptic pyramidal neurons to the observed effect of RA on inhibitory synaptic transmission, we selectively deleted RARα in one or the other neuronal cell types. Our results showed RARα expression in parvalbumin (PV)-expressing interneurons is required for RA-induced reduction in mIPSC onto pyramidal neurons.
One advantage of studying synaptic plasticity in the visual system is visual inputs can be easily manipulated in intact animals, and prolonged visual deprivation can reliably induce homeostatic synaptic plasticity. We thus induced visual deprivation by binocular enucleation, which blocks all visual inputs into V1. This manipulation has been reported to induce robust homeostatic synaptic plasticity.
Three days of visual deprivation led to a dramatic reduction in synaptic inhibition onto L2/3 pyramidal neurons, much like the effect of direct RA treatment. Importantly, deletion of RARα in PV-expressing interneurons, which blocked RA’s effect on synaptic inhibition, also prevented visual deprivation-induced reduction in mIPSCs, suggesting synaptic RA/RARα signaling mediates homeostatic plasticity at inhibitory synapses in the visual cortical circuits.
Many neurodevelopmental disorders are associated with profound deficits in synaptic plasticity. Our previous work investigating synaptic defects in fragile X syndrome (FXS) demonstrated synaptic RA signaling and homeostatic plasticity are severely impaired in neurons derived from FXS human patients, as well as in hippocampal neurons of FXS-model mice, which lack fragile X mental retardation protein (FMRP).
We were therefore curious whether synaptic RA signaling is also impaired in visual cortical circuits of the FXS mouse.
Indeed, deletion of FMRP in the whole animal blocked RA- and visual deprivation-induced reduction in synaptic inhibition onto L2/3 pyramidal neurons. The effects of RA and visual deprivation on synaptic inhibition were also prevented when FMRP was specifically deleted in PV-expressing neurons. These results suggest intact function of both FMRP and RARα in PV-expressing interneurons is required for inhibitory homeostatic synaptic plasticity in the visual cortex.
Taken together, our results demonstrated synaptic RA signaling is an essential synaptic mechanism in vivo. Sensory experience-induced homeostatic synaptic plasticity in visual cortex is achieved at least in part by engaging synaptic RA signaling. Moreover, we provided in vivo evidence that RA-dependent homeostatic plasticity is severely compromised in the FXS mouse, and that FMRP and RARα act cell-autonomously in PV-expressing interneurons to support homeostatic changes at cortical inhibitory synapses.
These results not only validated our previous findings from in vitro studies but also raised new questions.
For example, how does RA operate in presynaptic interneurons to regulate synaptic transmission? What is the molecular nature of the interaction between FMRP and RARα?
Answering these questions will not only further our understanding of molecular mechanisms of homeostatic plasticity but also may open up new possibilities for future studies investigating drug targets for developmental disorders such as FXS.
Retinoic Acid Receptor RARα-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex. Lei R. Zhong, Xin Chen, Esther Park, Thomas C. Südhof, Lu Chen. JNeurosci Dec 2018, 38 (49) 10454–10466; DOI: 10.1523/JNEUROSCI.1133-18.2018