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

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

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 GABA_B receptors and ensure high release probability at GABA synapses. GATs in combination with GABA_B receptors also curtail extrasynaptic GABA_A R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABA_A 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.