We investigated the effects of the endocannabinoid-mediated neuron-astrocyte signalling on synaptic transmission in mouse hippocampal slices.

We recorded from CA1 pyramidal neurons and monitored astrocyte Ca²⁺ levels. We stimulated Schaffer collateral single synapses. Endocannabinoids (ECBs) were released by neuron depolarization (ND) while EPSCs were monitored in an adjacent neuron. We found:

1) ND transiently increased the probability of transmitter release (Pr) in 40% of the synapses, without affecting EPSC amplitudes, which resulted in a short-term potentiation (e-STP). These effects were abolished by AM251, and were absent in CB1R^-/- mice.

2) In 27% of the synapses, ND transiently decreased Pr without changing EPSC amplitudes. This was blocked by AM251 and was absent in CB1R^-/- mice, like depolarization-induced suppression of excitation (DSE).

3) ND elevated Ca²⁺ in astrocytes, which was abolished by AM251 and were absent in CB1R^-/- mice.

4) ND-evoked ECB-mediated e-STP and astrocyte Ca²⁺ signal were unaffected by pertussis toxin, but were blocked by phospholipase-C antagonists and thapsigargin, indicating that they were not mediated by G_i/o proteins, but by G_q/11 proteins and phospholipase-C-mediated Ca²⁺ mobilization from internal stores.

5) After loading astrocytes with BAPTA, DSE was unaffected, but ND failed to induce e-STP.

6) The ND-evoked e-STP was abolished by the type I mGluR antagonists.

7) Synapses that showed ND-evoked synaptic potentiation were depressed by CB1R agonists.

8) When pairing the ND-evoked ECB-mediated astrocytic Ca²⁺ signal with a mild postsynaptic depolarization, the transient potentiation became persistent.

We conclude that endocannabinoids potentiate excitatory synaptic transmission through stimulation of Ca²⁺-dependent release of glutamate from astrocytes.

Funded by MICINN (BFU2007-064764) Spain, and EU (HEALTH-F2-2007-202167).