Lack of the Transient Receptor Potential Vanilloid 1 Shifts Cannabinoid-Dependent Excitatory Synaptic Plasticity in the Dentate Gyrus of the Mouse Brain Hippocampus.

Jon Egaña-Huguet,Miquel Saumell-Esnaola,Sergio Barrondo,Inmaculada Gerrikagoitia,Gontzal García Del Caño,Edgar Soria-Gomez,Nagore Puente,Svein Achicallende,Joan Sallés,Izaskun Elezgarai,Pedro Grandes,Itziar Bonilla-Del Río

doi:10.3389/fnana.2021.701573

Abstract

The transient receptor potential vanilloid 1 (TRPV1) participates in synaptic functions in the brain. In the dentate gyrus, post-synaptic TRPV1 in the granule cell (GC) dendritic spines mediates a type of long-term depression (LTD) of the excitatory medial perforant path (MPP) synapses independent of pre-synaptic cannabinoid CB1 receptors. As CB1 receptors also mediate LTD at these synapses, both CB1 and TRPV1 might be influencing the activity of each other acting from opposite synaptic sites. We tested this hypothesis in the MPP–GC synapses of mice lacking TRPV1 (TRPV1-/-). Unlike wild-type (WT) mice, low-frequency stimulation (10 min at 10 Hz) of TRPV1-/- MPP fibers elicited a form of long-term potentiation (LTP) that was dependent on (1) CB1 receptors, (2) the endocannabinoid 2-arachidonoylglycerol (2-AG), (3) rearrangement of actin filaments, and (4) nitric oxide signaling. These functional changes were associated with an increase in the maximum binding efficacy of guanosine-5′-O-(3-[35S]thiotriphosphate) ([35S]GTPγS) stimulated by the CB1 receptor agonist CP 55,940, and a significant decrease in receptor basal activation in the TRPV1-/- hippocampus. Finally, TRPV1-/- hippocampal synaptosomes showed an augmented level of the guanine nucleotide-binding (G) Gαi1, Gαi2, and Gαi3 protein alpha subunits. Altogether, the lack of TRPV1 modifies CB1 receptor signaling in the dentate gyrus and causes the shift from CB1 receptor-mediated LTD to LTP at the MPP–GC synapses.

Highlights

Cannabinoid functions in the brain are typically associated with the activation of cannabinoid CB1 receptors (Kano et al, 2009; Katona and Freund, 2012; Pertwee, 2015; Lu and Mackie, 2016)
These data suggest that transient receptor potential vanilloid 1 (TRPV1) blockade can shift the CB1 receptor-dependent long-term depression (LTD) to longterm potentiation (LTP) elicited by Low-frequency stimulation (LFS) of medial perforant path (MPP)
If the data were not normalized to their corresponding basal values, Emax differences were not statistically significant. The aim of this investigation was to study the impact of the genetic deletion of TRPV1 on the CB1 receptor functionality and synaptic plasticity in the hippocampal dentate gyrus

Summary

Introduction

Cannabinoid functions in the brain are typically associated with the activation of cannabinoid CB1 receptors (Kano et al, 2009; Katona and Freund, 2012; Pertwee, 2015; Lu and Mackie, 2016). Several cannabinoid effects depend on the activation of members of the transient receptor potential (TRP) channel family (De Petrocellis et al, 2011; Morales and Reggio, 2017; Muller et al, 2019). In the hippocampus, functional TRPV1 receptors in the long term depress excitatory pyramidal cell– interneuron synapses (Gibson et al, 2008), and pre-synaptic TRPV1 facilitates the release of glutamate at the excitatory synaptic terminals in the CA1 hippocampus (Bialecki et al, 2020). Thereby, like in other brain regions (Lafourcade et al, 2007; Grueter et al, 2010; Puente et al, 2011), long-term depression (LTD) at medial perforant path (MPP) synapses is mediated by post-synaptic TRPV1 activity (Chávez et al, 2010) and CB1 receptor signaling (Peñasco et al, 2019; Fontaine et al, 2020). The constitutive absence of TRPV1 in mice alters the principal degrading enzymes of 2-AG and anandamide (AEA, the other main endocannabinoid), as well as modifies CB1 receptors

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Conclusion