2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression
of synaptic transmission in the brain. 2-AG is synthesized in activated postsynaptic
neurons by sn-1-specific diacylglycerol lipase (DGL), binds to presynaptic cannabinoid
CB(1) receptors, suppresses neurotransmitter release, and is degraded mainly by monoacylglycerol
lipase (MGL). In the basolateral amygdala complex, it has been demonstrated that CB(1)
is particularly enriched in axon terminals of cholecystokinin (CCK)-positive GABAergic
interneurons, induces short- and long-term depression at inhibitory synapses, and
is involved in extinction of fear memory. Here, we clarified a unique molecular convergence
of DGLalpha, CB(1), and MGL at specific inhibitory synapses in the basal nucleus (BA),
but not lateral nucleus, of the basolateral amygdala. The synapses, termed invaginating
synapses, consisted of conventional symmetrical contact and unique perisynaptic invagination
of nerve terminals into perikarya. At invaginating synapses, DGLalpha was preferentially
recruited to concave somatic membrane of postsynaptic pyramidal neurons, whereas invaginating
presynaptic terminals highly expressed CB(1), MGL, and CCK. No such molecular convergence
was seen for flat perisomatic synapses made by parvalbumin-positive interneurons.
On the other hand, DGLalpha and CB(1) were expressed weakly at axospinous excitatory
synapses. Consistent with these morphological data, thresholds for DGLalpha-mediated
depolarization-induced retrograde suppression were much lower for inhibitory synapses
than for excitatory synapses in BA pyramidal neurons. Moreover, depolarization-induced
suppression was readily saturated for inhibition, but never for excitation. These
findings suggest that perisomatic inhibition by invaginating synapses is a key target
of 2-AG-mediated control of the excitability of BA pyramidal neurons.