Gonadotropin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood-brain barrier

GnRH neurons project axons to the median eminence to control pituitary release of gonadotropins and, as such, represent the principal output neurons of the neuronal network controlling fertility. It is well established that the GnRH neurons exhibit a simple bipolar morphology with one or two long dendrites. Using adult GnRH-green fluorescent protein transgenic mice and juxtacellular cell filling, we report here that a subpopulation of GnRH neurons located in the rostral preoptic area exhibit extremely complex branching dendritic trees that fill the organum vasculosum of the lamina terminalis (OVLT). The dendritic nature of these processes was demonstrated at both light and electron microscopic levels by the presence of spines, dendritic ultrastructure, and synapses. Further, electrophysiological recordings showed that GnRH neurons were excited by glutamate as well as kisspeptin puffed onto their dendrites located within the OVLT. Using iv injection of horseradish peroxidase, a molecule unable to penetrate the blood-brain barrier (BBB), we show that GnRH neuron cell bodies and dendrites within 100 μm of the OVLT reside outside the BBB. Approximately 85% of GnRH neurons in this area express c-Fos at the time of the GnRH surge. These observations demonstrate that GnRH neurons extend complex, highly branched dendritic trees beyond the BBB into the OVLT, where they will be able to sense directly molecules circulating in the bloodstream. This indicates a new mechanism for the modulation of GnRH neurons that extends considerably the range of factors that are integrated by these neurons for the control of fertility.