The intricate tapestry of the brain relies on a complex web of signaling pathways among its neurons. At the heart of this neural symphony is glutamatergic signaling.Glutamatergic control of striatal activity is essential for several brain functions.Abnormal glutamatergic signaling is associated with several pathological conditions including Huntington’s disease (HD), a rare neurological disease marked by striatal dysfunction and degeneration.Compromised retinoic acid receptor beta (RARβ) signaling observed in the striatum of HD patients and mice models has been suggested to critically contribute to HD physiopathology.Accordingly, genomic and functional analyses of RARβ loss of function in the striatum revealed that this ligand-controlled transcription factor is a potential top regulator responsible for a vast array of transcriptional changes observed in HD striatum.Furthermore, mice carrying null mutation of RARβ(RARβKO-/-) displays selective dysfunction and loss of a subpopulation of medium spiny neurons expressing dopamine D2 receptor.The mechanism of such vulnerability is not known, however, in vitro studies suggested that it may involve enhanced sensitivity to glutamatergic neurotoxicity.To address this point, we have studied striatal synaptosome in RARβKO-/- mice using proteomics-based approach. We identified significant changes of glutamatergic pre- and post-synaptic proteins related to glutamatergic synapse of cortico-striatal projection neurons and cholinergic interneurons. Morphological vs molecular mechanisms of this enrichment will be discussed, as well as their functional relevance for behavioral consequences of RARβ deletion which include hyperactivity and motor coordination deficits.These findings might provide further insight into mechanisms of HD physiopathology but also MCOPS12, a rare neurologic disease caused by point mutations of RARβ.