Homeostatic synaptic plasticity (HSP) is a form on non-Hebbian plasticity that allows neurons to sense their global level of activity and modulate their own function to keep firing rate within a working range. In particular, 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). 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 activity. In neurons, global 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.
In this dissertation I demonstrate the critical role that translational regulation operated by RA plays in synaptic scaling, a post-synaptic form of homeostatic plasticity which consists in the regulation of receptor abundance on the post-synaptic membrane in response to activity blockade. In this context, my work has focused on the regulation of both excitatory and inhibitory transmission operated by RA in order to elucidate whether this molecule, normally only associated with neural development, plays a pivotal role in the modulation of excitation and inhibition balance in the adult brain. Since, abnormalities in this balance have been linked to several pathological conditions such as autism and Fragile-X mental retardation, my work described here emphasizes the primary role of the dynamic regulation of the excitation/inhibition balance in neural networks mediated by RA.