Sodium valproate alters GnRH-GABA interactions during development in seizure-prone mice

During reproductive maturation, characteristic changes occur in the morphology of the gonadotropin releasing hormone (GnRH) cell population within the hypothalamus. In the early stages of development, GnRH neurons are bipolar cells; however, just before pubertal onset, the majority of these neurons transform into unipolar cells. Our laboratory has reported that valproic acid (VPA), an antiepileptic medication that has previously been shown to slow the velocity of pubertal development in both humans and seizure-prone mice, is capable of delaying the normal process of GnRH morphological differentiation. As VPA is primarily believed to act via a GABAergic mechanism, the present study investigated potential influences of VPA on GnRH-GABA interactions within the medial preoptic area (mPOA) across pubertal development (experiment 1), as well as in adult animals (experiment 2). The results from experiment 1 revealed the expected drug effects on GnRH cell morphology. For VPA animals, there was a greater percentage of bipolar neurons at every time period except for the 24-day sample. Additionally, VPA animals had greater numbers of bipolar and unipolar GnRH neurons with GABA associations across all ages. However, experiment 2 showed a lack of drug effects on GnRH-GABA interactions in adulthood. These results suggest that VPA may delay GnRH cell morphological maturation by altering the density of GABAergic inputs to GnRH neurons. These inputs may normally play a role in timing the activation of the GnRH pulse generator. However, any neuroendocrine effects of VPA in adulthood are most likely due to the actions of VPA at another level of the hypothalamic-pituitary-gonadal axis.