Figure 3: Possible mechanisms for the modulation of GnRH secreting neurons by eCBs. (a) GABAergic modulation of GnRH secreting neurons. GnRH secreting neurons release eCBs that, as retrograde signals, directly act on CB1 located on GABAergic presynaptic neurons and inhibit the release of GABA; as a consequence, GnRH secreting neurons do not receive GABAergic input and do not release the GnRH. (b) Possible involvement of glial cells in eCBs/GABA/GnRH circuitry. Glutamate release by GnRH neurons may stimulate astrocytes to produce prostaglandins which in turn induce the synthesis of eCBs and/or the exposure of presynaptic CB1, thus modulating GABA release. (c) Hypothesis: are there neuronal systems other than GABAergic able to modulate endocannabinoid/GnRH crosstalk? Kisspeptins stimulate gonadotropin discharge in several species modulating the activity of GnRH secreting neurons via the activation of GPR54 receptor located on GnRH neurons. Might AEA also act as retrograde signal upon kisspeptin neurons in order to suppress GnRH secretion?