Dysfunction of the RAR/RXR Signaling Pathway in the Mouse Forebrain Reduces GluA1, PSD-95, and ARP3 Expression in the Hippocampus.

Retinoic acid (RA), a biologically active metabolite of vitamin A, regulates gene expression through retinoic acid receptor/retinoid X receptor (RAR/RXR)-dependent transcription and is important for various biological phenomena. To understand the role of forebrain RA signaling in synaptic plasticity and memory, we generated transgenic mice expressing a dominant-negative form of retinoic acid receptor α (dnRARα) in adult forebrain. We previously showed that dnRARα expression in the adult forebrain impairs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission and long-term potentiation (LTP) in hippocampal CA1 neurons and hippocampus-dependent memory. To investigate the molecular basis of these impairments, we here examined expressions of synaptic plasticity-related molecules in the hippocampus of dnRARα mice. We found that protein levels of GluA1 and postsynaptic density protein 95 (PSD-95) were significantly reduced in the hippocampus of dnRARα mice in a dnRARα expression-dependent manner. To further examine protein expression changes in dnRARα mice, we performed proteome analysis and found that expression of actin-related protein 3 (ARP3), a molecule implicated in activity-dependent spine enlargement and maturation, was also reduced. Combined with our previous findings, these results suggest that forebrain RAR/RXR signaling is crucial for maintaining synaptic transmission, plasticity, and memory formation by upregulating GluA1, PSD-95, and ARP3.