Glutamatergic Input From Arcuate Nucleus Kiss1 Neurons to Preoptic Kiss1 Neurons Is Required for LH Surge in Female Mice.

Summary

Estradiol upregulates Vglut2 and excitatory conductances in arcuate Kiss1 neurons, boosting glutamate release. Optogenetic activation of these neurons excites preoptic Kiss1 neurons via ionotropic and metabotropic glutamate receptors, and CRISPR deletion of Vglut2 in arcuate Kiss1 neurons abolishes the estrogen-induced LH surge and reduces corpora lutea.

Key Findings

• Estradiol increases Vglut2 expression and excitability in arcuate Kiss1 neurons, enhancing glutamate release.
• Optogenetic stimulation of arcuate Kiss1 neurons excites preoptic Kiss1 neurons via ionotropic and metabotropic glutamate receptors.
• CRISPR mutagenesis of Vglut2 in arcuate Kiss1 neurons abolishes the estrogen-induced LH surge and reduces corpora lutea formation.

Clinical Implications

Identifies glutamatergic signaling between kisspeptin populations as a potential therapeutic target for anovulation and infertility. May inform strategies modulating excitatory inputs in hypothalamic circuits.

Limitations

• Findings in mice may not directly translate to humans; species differences need consideration
• Focus on female estrous stage; broader endocrine states and neuromodulators require evaluation

Future Directions

Test whether modulating glutamatergic inputs rescues ovulatory defects in disease models and explore pharmacologic modulation of VGLUT2-dependent signaling in reproductive disorders.