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

Abstract

Although endocannabinoids have emerged as essential retrograde messengers in several forms of synaptic plasticity, it remains controversial whether they mediate long-term depression (LTD) of glutamatergic synapses onto excitatory and inhibitory neurons in the hippocampus. Here we show that parvalbumin- and somatostatin/metabotropic glutamate receptor 1a (mGlu1a)-positive GABAergic interneurons express diacylglycerol lipase-α (DGL-α), a synthesizing enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), albeit at lower levels than principal cells. Moreover, this lipase accumulates postsynaptically around afferent excitatory synapses in all three cell types. To address the role of retrograde 2-AG-signaling in LTD, we investigated two forms: (1) produced by postsynaptic spiking paired with subsequent presynaptic stimulation or (2) induced by group I mGlu activation by DHPG. Neither form of LTD was evoked in the presence of the mGlu5 antagonist MPEP, the DGL inhibitor THL or the intracellularly applied Ca2+ chelator BAPTA in CA1 pyramidal cells, fast-spiking interneurons (representing parvalbumin-containing cells) and interneurons projecting to stratum lacunosum-moleculare (representing somatostatin/mGlu1a-expressing interneurons). Both forms of LTD were completely absent in CB1 cannabinoid receptor knockout mice, whereas pharmacological blockade of CB1 led to inconsistent results. Notably, in accordance with their lower DGL-α level, a higher stimulation frequency or higher DHPG concentration was required for LTD induction in interneurons compared to pyramidal cells. These findings demonstrate that hippocampal principal cells and interneurons produce endocannabinoids to mediate LTD in a qualitatively similar, but quantitatively different manner. The shifted induction threshold implies that endocannabinoid-LTD contributes to cortical information processing during distinct network activity patterns in a cell type-specific manner.

Joint CP-AMPA and group I mGlu receptor activation is required for synaptic plasticity in dentate gyrus fast-spiking interneurons

“…4I), which is activated by Ca 2+ and G protein signaling via phospholipase C and diacylglycerol (26). Our results are in contrast to results found with CA1 PIIs, where mGluR-evoked endocannabinoid release induces LTD (27), a mechanism that is absent at MF-PII synapses, very likely due to the lack of presynaptic cannabinoid receptors (28).…”

Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex

“…To test this, we performed experiments applying high frequency bursts of APs (5 APs at 40 Hz, x 40 with 0.5 s interval) in the presynaptic PC after a baseline of EPSPs (at least 5 min, but less than 10 min, analyzed including failures) [26,27]. Postsynaptic FSINs (SW 0.40 ± 0.02 ms) were held in resting membrane potential in current clamp (–67.6 ± 2.2 mV, n = 9) (Fig 2).…”

Endogenous cannabinoid signaling at inhibitory interneurons

“…At striatal [51], nucleus accumbens [52], visual [45] and somatosensory [53] cortical (but see [54]) fast-spiking interneuron output synapses, CB 1 Rs were shown to mediate short-term plasticity. In addition, hippocampal fast-spiking interneurons can mobilize eCBs required for long-term plasticity [55]. Beyond retrograde signaling, evidence indicates 2-AG can engage postsynaptic CB 1 Rs in an autocrine fashion to inhibit cortical interneuron excitability [56,57].…”