Food and fertility

It is well known that starvation reduces fertility, and this makes sense from an evolutionary perspective because it is disadvantageous to produce large numbers of offspring when food supplies are scarce. What is the neurobiological basis of the link between feeding and fertility? Reporting in the Journal of Neuroscience, Sullivan et al. provide some new insights.

The hypothalamic gonadotropin-releasing hormone (GnRH) neurons provide a crucial neuroendocrine interface between the brain and the reproductive organs. The GnRH neurons receive input from γ-aminobutyric acid (GABA)-releasing neurons. GABA is usually an inhibitory neurotransmitter for adult neurons, but it is excitatory for GnRH neurons.

Sullivan et al. initially hypothesized that fasting converts the GABA-mediated excitation of GnRH neurons to inhibition. However, this was not borne out by their findings. After a 48-hour fast in female mice (which is sufficient to halt the progression of the reproductive cycle), GABA_A receptor activation was still excitatory. The authors next asked whether the activity of presynaptic GABA neurons was changed by fasting. After fasting, the GnRH neurons still showed spontaneous GABA-mediated excitatory postsynaptic currents (sPSCs), but the frequency was reduced. Some GABA-releasing neurons express receptors for the satiety hormone leptin, and the authors showed that treating animals with leptin could reverse the effects of fasting on sPSC frequency.

There is also evidence that leptin potentiates the response of GnRH neurons to GABA_A receptor activation. Sullivan et al. measured miniature PSCs (mPSCs) in brain slices from fed mice. The slices were treated with leptin, and also with tetrodotoxin to block activity-dependent signals from the presynaptic terminal. The authors found that leptin did not affect the frequency of mPSCs, but it increased their amplitude, rate of rise and decay times.

So, GABA-releasing neurons relay information about fuel availability to the GnRH neurons. The effect of leptin seems to be twofold — it promotes GABA release from the presynaptic terminal, and it makes the postsynaptic GnRH cell more responsive to GABA. It remains to be shown whether GnRH neurons express leptin receptors, although the functional data are consistent with such a possibility. Hypothalamic dysfunction is often associated with infertility in humans, and Sullivan et al. speculate that understanding how GABA-mediated neurotransmission is modulated in GnRH neurons could aid the development of new therapeutic approaches to treat infertility.