Evaluation of the importance of GABAergic and dopaminergic transmission in neurons that express the growth hormone-releasing hormone to the control of GH secretion

Abstract

The GH pituitary secretion is regulated by negative feedback loops via hypothalamic neurons. In this regard, hypothalamic neurons that produce GHRH act by stimulating GH synthesis, whereas somatostatin (SST) acts as GH secretion inhibitor. However, only a small portion of the GHRH neurons express GH receptor (GHR) (Wasinski et al., J Neurosci 40: 4309-4322, 2020). In addition, our research group has a article under review showing that SST neurons do not regulate the pulsatile pattern of GH secretion through negative feedback (dos Santos et al., manuscript under review in the Neuron Journal). Thus, other neural populations must be involved in this control. We recently demonstrated that neurons that produce both dopamine and GABA are key regulators in controlling GH secretion via negative feedback (Wasinski et al., J Neurosci 40: 4309-4322, 2020; dos Santos et al., manuscript under review in the Neuron Journal). Of note, previous studies have shown that D2 dopamine receptor (D2R) knockout mice, non-specific and neuron-specific, exhibit reductions in GH secretion and hypothalamic GHRH mRNA leading to dwarfism (Diaz-Torga et al., Endocrinology 143:1270-1279, 2002; Noain et al., J Neurosci 33:5834-5842, 2013). To confirm those previous findings and determine whether dopaminergic/GABAergic transmission acts through GHRH neurons to affect GH secretion, we propose unprecedented and promising experiments aimed at block GABAergic transmission from dopaminergic neurons and also inactivating dopamine D2R from GHRH neurons. These findings may revolutionize the understanding of the neuroendocrine control of the somatotropic axis and consequently of the hypothalamic mechanisms that control body growth.It is worth noting that the work plan for this scholarship includes experiments proposed in the following subprojects of the thematic research grant approved by FAPESP: *subproject 4: evaluation of the importance of GABAergic and glutamatergic neurons in the control of GH secretion by negative feedback; *subproject 5: evaluation of the importance of GABAergic transmission in somatostatin neurons on the control of GH secretion; *subproject 6: action of dopaminergic transmission in GHRH expressing neurons to the control of GH secretion. (AU)