A novel non‐CB1/TRPV1 endocannabinoid‐mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons

Abstract

Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well the involvement of group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analogue R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by approximately 50%. The group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10μM) but not by the mGluR1 antagonist CPCCOEt (50 μM). Interestingly, however, neither DHPG-mediated nor Rmethanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 μM), the CB1 antagonist AM-251 (2 μM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.

A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity

“…In a previous study, our lab identified an anandamide‐mediated plasticity that was independent of CB1 and TRPV1 (Edwards et al, ). Therefore, we chose to examine GPR55 as a candidate for this effect based on its ability to bind eCBs such as anandamide and the fact that lysophosphatidylinositol has never been examined for its role in plasticity that we know of.…”

The GABAAreceptor agonist muscimol induces an age- and region-dependent form of long-term depression in the mouse striatum

“…However, this compound and endocannabinoids might modify synaptic transmission and induce synaptic plasticity through CB1 receptorindependent actions (Edwards et al 2012;Golovko et al 2015). We have performed several sets of experiments to examine this possibility.…”

Endocannabinoid-Mediated Long-Term Depression of Afferent Excitatory Synapses in Hippocampal Pyramidal Cells and GABAergic Interneurons

“…LTD of glutamatergic inputs onto hippocampal interneurons can also be triggered by several induction protocols (McMahon and Kauer, 1997; Laezza et al, 1999; Gibson et al, 2008; Nissen et al, 2010; Le Duigou et al, 2011; Edwards et al, 2012). When tested, LTD in cortical GABAergic interneurons was found to be insensitive to treatment with CB 1 antagonists (Lu et al, 2007; Gibson et al, 2008; Edwards et al, 2010; Le Duigou et al, 2011), which was surprising, because synthetic cannabinoid ligands effectively suppress excitatory inputs onto hippocampal interneurons including fast-spiking basket cells (Gibson et al, 2008; Holderith et al, 2011).…”

“…Despite its high postsynaptic concentration opposing presynaptic CB 1 cannabinoid receptors at excitatory synapses of hippocampal principal cells (Katona et al, 2006; Yoshida et al, 2006), and tight coupling of group I mGlu-activation to 2-AG mobilization (Jung et al, 2005), mGlu-dependent LTD at hippocampal excitatory synapses is generally considered to be endocannabinoid-independent in principal cells (Rouach and Nicoll, 2003; Nosyreva and Huber, 2005; Lante et al, 2006). Similarly, excitatory synapses onto hippocampal and other cortical interneurons can readily undergo LTD (McMahon and Kauer, 1997; Laezza et al, 1999; Lu et al, 2007; Gibson et al, 2008; Nissen et al, 2010; Le Duigou et al, 2011; Edwards et al, 2012), but DGL-α has not yet been reported in GABAergic interneurons, and pharmacological experiments suggest that LTD in cortical interneurons may not require endocannabinoid signaling (Lu et al, 2007; Gibson et al, 2008; Le Duigou et al, 2011; Edwards et al, 2012). …”