Somatostatin triggers rhythmic electrical firing in hypothalamic GHRH neurons

Abstract

Hypothalamic growth hormone-releasing hormone (GHRH) neurons orchestrate body growth/maturation and have been implicated in feeding responses and ageing. However, the electrical patterns that dictate GHRH neuron functions have remained elusive. Since the inhibitory neuropeptide somatostatin (SST) is considered to be a primary oscillator of the GH axis, we examined its acute effects on GHRH neurons in brain slices from male and female GHRH-GFP mice. At the cellular level, SST irregularly suppressed GHRH neuron electrical activity, leading to slow oscillations at the population level. This resulted from an initial inhibitory action at the GHRH neuron level via K+ channel activation, followed by a delayed, sst1/sst2 receptor-dependent unbalancing of glutamatergic and GABAergic synaptic inputs. The oscillation patterns induced by SST were sexually dimorphic, and could be explained by differential actions of SST on both GABAergic and glutamatergic currents. Thus, a tripartite neuronal circuit involving a fast hyperpolarization and a dual regulation of synaptic inputs appeared sufficient in pacing the activity of the GHRH neuronal population. These “feed-forward loops” may represent basic building blocks involved in the regulation of GHRH release and its downstream sexual specific functions.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

“…This observation may explain lower basal GH levels in male than in female mammals ( Jansson et al, 1985 ), and also the sexually dimorphic GH pulsatile secretion ( Low et al, 2001 ). More recently, the negative regulation by SRIF of GHRH neuron electrical activity was decrypted using a GHRH–GFP transgenic model ( Osterstock et al, 2016 ). It revealed a sexual dimorphism, which is primarily attributable to a sex-dependent control of GABAergic and glutamatergic inputs by SRIF, rather than intrinsic differences in the GHRH neurons themselves.…”

“…Intriguingly, this is the opposite for SRIF inhibition of GABAergic (negative) inputs, being especially robust and synchronized in males. Both SST 1 and SST 2 are involved in GHRH neuron rhythmicity, but SST 1 receptors specifically transduce SRIF inhibitory control of GABAergic inputs, likely taking place at the presynaptic level ( Osterstock et al, 2016 ). Seven percent of neuropeptide Y–positive neurons in the ARC coexpress SST 1 mRNA, suggesting a direct interaction between the somatotropic axis and neuroendocrine regulatory loops of energy homeostasis ( Fodor et al, 2005 ).…”

Central Control of Feeding Behavior by the Secretin, PACAP, and Glucagon Family of Peptides

“…Transcriptional profiling of hypothalamic glucose-sensing neurons along with electrophysiological studies has revealed that hypoglycemia activated GHRH neurons ( 195 ). The electrical patterns that controlled the hypothalamic GHRH neurons have remained elusive while recently somatostatin has been found to bring about irregular suppression of the neuronal activity of GHRH neurons ( 196 ). In summary, it is the important role in GH secretion along with its involvement in nutritional and circadian feeding behavior that has made GHRH vital in integration and coordination of diverse aspects related to metabolism, growth and nutrient regulation ( 190 , 197 ).…”

A Comparative Update on the Neuroendocrine Regulation of Growth Hormone in Vertebrates

“…However, results from other mammals, including female rats [Reviewed by Gahete et al ( 38 )], challenge the role of somatostatin in regulating GH rhythmicity. More recently, it has been demonstrated that somatostatin irregularly inhibits GHRH neurons in male and female mice, inducing sex–specific oscillatory patterns in the GHRH neural electrical activity ( 86 ). The sexual dimorphism in the GHRH oscillatory patterns induced by somatostatin seems dependent on the different actions of both glutamate and GABA neurons, and these differences could explain the distinctive GH secretion pattern between male and female mice ( 86 ).…”