Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation

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Abstract
Endocannabinoids are retrograde messengers that are released from central neurons by depolarization‐induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole‐cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)‐3,5‐dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212–2, suppressed IPSCs in all DHPG‐sensitive pairs but not in most of DHPG‐insensitive pairs. The effects of both DHPG and WIN55,212–2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization‐induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization‐induced and group I mGluR‐induced endocannabinoid release. DHPG caused no change in depolarization‐induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.