Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons

J Physiol. 2018 May 15;596(10):1919-1929. doi: 10.1113/JP275588. Epub 2018 Mar 14.

Abstract

Key points: GABA transporter (GAT) blockade recruits extrasynaptic GABAA receptors (GABAA Rs) and amplifies constitutive presynaptic GABAB R activity. Extrasynaptic GABAA Rs contribute to a tonic current. Corticosteroids increase the tonic current mediated by extrasynaptic GABAA Rs.

Abstract: Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABAB receptors and ensure high release probability at GABA synapses. GATs in combination with GABAB receptors also curtail extrasynaptic GABAA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABAA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

Keywords: CRH; GABA; GABA receptor; PVN; electrophysiology; extrasynaptic; hypothalamus; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Corticosterone / pharmacology*
  • Corticotropin-Releasing Hormone / metabolism*
  • Female
  • GABA Plasma Membrane Transport Proteins / physiology*
  • Inhibitory Postsynaptic Potentials*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Inhibition*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / physiology*
  • Receptors, GABA-A / metabolism
  • Receptors, GABA-B / metabolism
  • Synapses / physiology

Substances

  • Anti-Inflammatory Agents
  • GABA Plasma Membrane Transport Proteins
  • Receptors, GABA-A
  • Receptors, GABA-B
  • Slc6a1 protein, mouse
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone

Grant support