Figure 6. Possible models for the differential regulation of GnRH release in the POA and ME.

In the POA (left), GnRH release can occur without action potentials and can be locally inhibited by GnIH. We postulate all the elements necessary for control may be contained locally within the GnRH process itself. It is important to point out that influences from afferent neurons are not excluded. For example, kisspeptin clearly influences release, likely via direct action on the neuronal process. In the ME (right), although kisspeptin can induce GnRH release in an action potential-independent manner, suggesting that the GnRH neuron itself does not need to generate spikes for secretion, regulation of GnRH release also appeared to depend more on the upstream network, because 1) elevating intracellular Ca²⁺ by blocking endoplasmic reticulum (ER) reuptake was unable to induce GnRH release in the absence of action potentials; 2) GnIH did not inhibit GnRH release locally, suggesting that it is sculpting secretory pattern via the network; and 3) it is likely that endogenous release of kisspeptin and other neuromodulators is action potential dependent. We hypothesize that by injecting kisspeptin locally the requirement for GnRH neuron action potential firing was bypassed and kisspeptin directly stimulated GnRH release from the GnRH terminal. SOCE, store-operated calcium entry.