Expression of type one cannabinoid receptor in different subpopulation of kisspeptin neurons and kisspeptin afferents to GnRH neurons in female mice

Abstract

The endocannabinoids have been shown to target the afferents of hypothalamic neurons via cannabinoid 1 receptor (CB1) and thereby to influence their excitability at various physiological and/or pathological processes. Kisspeptin (KP) neurons form afferents of multiple neuroendocrine cells and influence their activity via signaling through a variation of co-expressed classical neurotransmitters and neuropeptides. The differential potency of endocannabinoids to influence the release of classical transmitters or neuropeptides, and the ovarian cycle-dependent functioning of the endocannabinoid signaling in the gonadotropin-releasing hormone (GnRH) neurons initiated us to study whether (a) the different subpopulations of KP neurons express CB1 mRNAs, (b) the expression is influenced by estrogen, and (c) CB1-immunoreactivity is present in the KP afferents to GnRH neurons. The aim of the study was to investigate the site- and cell-specific expression of CB1 in female mice using multiple labeling in situ hybridization and immunofluorescent histochemical techniques. The results support that CB1 mRNAs are expressed by both the GABAergic and glutamatergic subpopulations of KP neurons, the receptor protein is detectable in two-thirds of the KP afferents to GnRH neurons, and the expression of CB1 mRNA shows an estrogen-dependency. The applied estrogen-treatment, known to induce proestrus, reduced the level of CB1 transcripts in the rostral periventricular area of the third ventricle and arcuate nucleus, and differently influenced its co-localization with vesicular GABA transporter or vesicular glutamate transporter-2 in KP neurons. This indicates a gonadal cycle-dependent role of endocannabinoid signaling in the neuronal circuits involving KP neurons.

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“…The secondary messengers inositol-1, 4, 5-trisphosphate and diacylglycerol as well as arrestin-1 and arrestin-2 contribute to hormone release [ 240 , 241 , 242 , 243 ]. While the ECS modulates the hypothalamic release of GnRH and has consequences on steroid biosynthesis in several species [ 198 ], and the expression of CB1-R has been reported in different subpopulations of kiss1 neurons in female mice [ 244 ], currently the possible correlation between the kisspeptin/GnRH system and the ECS has only been demonstrated in the hypothalamus and gonad of male amphibians [ 237 ]. Apart from the involvement in the hypothalamus the ECS also permits gametogenesis and extragonadic maturation of the male gamete [ 198 ].…”

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“…This result supported that neuronal CB1, mainly located in axon terminals of presynaptic neurons to GnRH neurons, participates in the inhibitory control of GnRH release in males. At the present, numerous studies have reported the effects of CB1 and TRPV1 signaling on GnRH modulators such as estradiol [ 53 ], kisspeptin [ 54 ], GABA [ 55 ], and ghrelin [ 56 ], among others.…”