CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control
synaptic communication and thereby circuit operation widespread in the CNS. Although
it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation,
the mechanisms of the decrease of GABA release upon activation of these cannabinoid
receptors remain elusive. To determine the mechanisms underlying the suppression of
synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs)
at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic
[Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function
with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)].
Altering CB1 function by either increasing endocannabinoid production or removing
its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting
Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels.
These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic
axon terminals by CB1, leading to the effective suppression of synaptic inhibition.
