Somatostatin triggers rhythmic electrical firing in hypothalamic GHRH neurons.

Guillaume Osterstock,Patrice Mollard,Manon Granier,Iain C A F Robinson,David J Hodson,Pierre Fontanaud,Danielle Carmignac,Alexander Barre,Violeta Mitutsova,Pierre-François Méry,Marine Chazalon,Nikolaus Plesnila,Malcolm J Low

doi:10.1038/srep24394

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.

Highlights

Hypothalamic growth hormone-releasing hormone (GHRH) neurons control the pulsatile secretion of growth hormone (GH) from the pituitary gland[1], thereby regulating growth and metabolism
We show that SST inhibited GHRH neuron electrical activity in brain slices from GHRH-GFP transgenic mice[8,9]
Acute somatostatinergic inhibition of GHRH neurons depends on GIRK activation

Summary

Introduction

Hypothalamic growth hormone-releasing hormone (GHRH) neurons control the pulsatile secretion of growth hormone (GH) from the pituitary gland[1], thereby regulating growth and metabolism. We show that SST inhibited GHRH neuron electrical activity in brain slices from GHRH-GFP transgenic mice[8,9] This inhibitory effect of SST was not sustained, leading to the emergence of oscillations in GHRH neuronal population activity. These firing patterns depend on a basic circuit consisting of: i) a neuropeptide input (SST); ii) a parvocellular neuronal target (GHRH neuron); and iii) neuronal inputs releasing GABA and glutamate that allow GHRH neurons to escape SST-blockade. This hitherto unidentified tripartite system may form coherent and incoherent feed-forward loops[12], which recur throughout the arcuate nucleus to promote rhythms in GHRH release in response to physiological demands

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Discussion

Conclusion