Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

The modifiability of neuronal response plasticity is called metaplasticity. In suppressing synaptic inhibition and facilitating induction of long-term excitatory synaptic plasticity, endocannabinoids (eCBs) act as agents of metaplasticity. We now report the discovery of a calcium-dependent mechanism that regulates eCB mobilization by metabotropic glutamate receptor (mGluR) activation. The switch-like mechanism primes cells to release eCBs and requires a transient rise in intracellular Ca2+ concentration ([Ca2+](i)) but not concurrent activation-of mGluRs. Conversely, short-term, [Ca2+](i-) dependent eCB release can be persistently enhanced by mGluR activation. Hence, eCBs are also objects of metaplasticity, subject to higher levels of physiological control.