All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

ABSTRACT The vitamin A derivative all-trans retinoic acid (atRA) is a key mediator of synaptic plasticity. Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. However, it remains unclear how atRA mediates brain region-specific effects on synaptic transmission and plasticity. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult male C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata. In contrast to what has been reported in other brain regions, no major changes in synaptic transmission were observed in the ventral and dorsal hippocampus 6 hours after atRA administration. Likewise, no evidence for changes in the intrinsic properties of hippocampal dentate granule cells was obtained in the atRA-treated group. Moreover, hippocampal transcriptome analysis revealed no essential changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, i.e., for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic transmission. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, thus extending our previous results on the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.