Endocannabinoid Modulation of Synaptic Inputs to Magnocellular Neurons

The effects of cannabinoids on physiology and behavior indicate that they affect hypothalamic function and the release of the neuropeptides oxytocin (OT) and vasopressin (VP) from the posterior pituitary. This suggests that endogenous cannabinoids modulate the activity of OT‐ and VP‐producing magnocellular neurons. Indeed, endocannabinoids (eCBs) can rapidly modulate synaptic transmission as they are released from depolarized postsynaptic neurons and thereafter diffuse retrogradely and bind to receptors located on presynaptic terminals to suppress the release of glutamate or GABA. Depolarization‐induced suppression of excitation (DSE) and depolarization‐induced suppression of inhibition (DSI) also occur at synapses on OT and VP magnocellular neurons. Since DSE is an activity‐dependent mechanism of synaptic modulation, it is hypothesized that it plays a role in shaping the phasic firing of VP neurons and the burst firing of OT neurons. The eCB release during phasic or burst spiking could temporarily induce the cessation of spiking by suppressing excitatory synaptic inputs. A second type of modulation, also mediated by the retrograde action of eCBs, is triggered by activation of G‐protein‐coupled receptors on the magnocellular neurons, for example, by the binding of glucocorticoids. The eCB‐mediated modulation of synapses on magnocellular neurons is dependent on physiological status. The eCBs released due to postsynaptic depolarization or glucocorticoids suppress glutamate but not GABA synaptic inputs under basal conditions. On the other hand, during physiologically induced glial retraction (e.g., during dehydration), DSI and glucocorticoid‐induced suppression of inhibition also emerge. This suggests a functional compartmentalization of glutamate and GABA synapses by glia. Thus, during basal conditions, glia may preferentially shield presynaptic GABAergic terminals from postsynaptic eCBs. Interestingly, eCBs mediate tonic suppression of GABA release under basal conditions. This duality is explained by the fact that one type of eCB, anandamide (AEA), appears to mediate the tonic suppression of GABA release, which is unrestricted by glia, whereas a second eCB, 2‐arachidonoylglycerol (2‐AG) appears to mediate the activity and glucocorticoid‐dependent suppression, which is affected by glial coverage. The versatility with which eCBs can modulate the synaptic inputs to magnocellular neurons suggests that they may play a prominent role in the control of OT and VP r