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

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.

Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions

“…This effect requires a BK–NMDA receptor complex rather than coupled BK–Cav channels, as Ca 2+ influx through NMDAR is required to activate BK channels [ 25 ]. A similar coupling between NMDAR and BK channels was also observed in basal dendrites of layer V pyramidal neurons in the barrel cortex, where they avoid the induction of spike-timing-dependent plasticity [ 188 ]. However, the BK–NMDAR complex is not observed in all basal dendrites from cortical neurons, where coupling between SK channels and NMDARs to regulate dendritic excitability has also been described [ 185 ].…”

Transient Receptor Potential Vanilloid 1 Function at Central Synapses in Health and Disease

“…The signaling pathways downstream of TRPV1 and CB1 receptor activation may be dynamically inter-regulated. Indeed, the lack of TRPV1 reportedly modifies the expression and localization of different components of the eCB system, causing a shift from CB1 receptor-mediated LTD to LTP in the dentate gyrus ( Egana-Huguet et al, 2021 ). While these results suggest an ability of eCBs to act through both CB1 and TRPV1 receptors, the factors that determine directionality of synaptic plasticity and functional consequences in behavior need to be determined.…”

Design and validation of recombinant protein standards for quantitative Western blot analysis of cannabinoid CB1 receptor density in cell membranes: an alternative to radioligand binding methods

“…The CB 1 receptor is a seven-transmembrane receptor [33][34][35] whose carboxy-terminal (C-terminal) tail facing the aqueous intracellular side possesses two unique properties that make it suitable to be used as a protein standard for quantitative Western blotting. On the one hand, it is predictable that it is stable in aqueous solution and, on the other hand, peptide sequences at its extreme end are against which the most reliable antibodies for the detection of the CB 1 receptor have been generated [14,30,[36][37][38]. Here, we designed, produced and purified recombinant protein standards comprising fragments of the cytosolic tail of the human CB 1 receptor and proved their suitability for the analysis of receptor density in cell membranes of the rat cerebral cortex by quantitative immunoblotting, as an alternative procedure to the use of radioligand binding assays.…”