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

Maximilian Lenz,Andreas Vlachos,Thomas Deller,Peter Jedlicka,Julia Muellerleile,Pia Kruse,Amelie Eichler

doi:10.7554/elife.71983

Maximilian Lenz, Andreas Vlachos + Show 5 more

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https://doi.org/10.7554/elife.71983

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Abstract

Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata-a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. 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, therefore, extending our previous results regarding 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.

Highlights

Adaptive processes in synaptic sites of the central nervous system are fundamental to normal brain function (Citri and Malenka, 2008; Humeau and Choquet, 2019; Neves et al, 2008)
Considering the role of the hippocampal formation, the role of the dentate gyrus, in memory acquisition (Hainmueller and Bartos, 2018), and based on previous work regarding the role of synaptopodin in synaptic plasticity (e.g., Galanis et al, 2021; Jedlicka et al, 2009; Paul et al, 2020; Vlachos et al, 2008; Yap et al, 2020), we studied the effects of all-trans retinoic acid (atRA) on synaptic transmission and plasticity and its link to synaptopodin in mouse dentate granule cells
We investigated the effects of systemic, that is, the intraperitoneal application of atRA on synaptic transmission and the plasticity of mature dentate granule cells in the adult hippocampus

Summary

Introduction

Adaptive processes in synaptic sites of the central nervous system are fundamental to normal brain function (Citri and Malenka, 2008; Humeau and Choquet, 2019; Neves et al, 2008). We showed that atRA potentiates excitatory postsynapses in human cortical slices prepared from neurosurgical access tissue (Lenz et al, 2021) This observation is consistent with previous reports suggesting that atRA mediates the accumulation of AMPA receptors at synaptic sites (Poon and Chen, 2008; Maghsoodi et al, 2008). We demonstrated that the presence of the plasticity-related protein synaptopodin, which is an essential component of the calcium ion-storing spine apparatus organelle (Deller et al, 2003; Mundel et al, 1997; Vlachos et al, 2013; Vlachos et al, 2009), is required for atRA-m ediated strengthening of excitatory neurotransmission in the mouse medial prefrontal cortex In accordance with these findings, atRA triggers structural changes of synaptopodin clusters, spine apparatuses, and dendritic spines in human cortical slices (Lenz et al, 2021). Considering the role of the hippocampal formation, the role of the dentate gyrus, in memory acquisition (Hainmueller and Bartos, 2018), and based on previous work regarding the role of synaptopodin in synaptic plasticity (e.g., Galanis et al, 2021; Jedlicka et al, 2009; Paul et al, 2020; Vlachos et al, 2008; Yap et al, 2020), we studied the effects of atRA on synaptic transmission and plasticity and its link to synaptopodin in mouse dentate granule cells

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