Tonic Extrasynaptic GABAA Receptor Currents Control Gonadotropin-Releasing Hormone Neuron Excitability in the Mouse

• DOI: 10.1210/en.2010-1191
• Publication Date: 2011-02-02T03:45:07Z
• Authors: Janardhan P. Bhat...; Seon Ah Park; Jin Bong Park; So Yeong Lee; Allan E. Herbison; Pan Dong Ryu; Seong Kyu Han
• Keywords: Male; Neurons; 0301 basic medicine; 0303 health sciences; Reverse Transcriptase Polymerase Chain Reaction; Brain; In Vitro Techniques; Receptors, GABA-A; Electrophysiology; Gonadotropin-Releasing Hormone; Mice; 03 medical and health sciences; Animals; Female; GABA-A Receptor Antagonists

Abstract It is well established that the GABAA receptor plays an important role in regulating the electrical excitability of GnRH neurons. Two different modes of GABAA receptor signaling exist: one mediated by synaptic receptors generating fast (phasic) postsynaptic currents and the other mediated by extrasynaptic receptors generating a persistent (tonic) current. Using GABAA receptor antagonists picrotoxin, bicuculline methiodide, and gabazine, which differentiate between phasic and tonic signaling, we found that ∼50% of GnRH neurons exhibit an approximately 15-pA tonic GABAA receptor current in the acute brain slice preparation. The blockade of either neuronal (NO711) or glial (SNAP-5114) GABA transporter activity within the brain slice revealed the presence of tonic GABA signaling in ∼90% of GnRH neurons. The GABAA receptor δ subunit is only found in extrasynaptic GABAA receptors. Using single-cell RT-PCR, GABAA receptor δ subunit mRNA was identified in GnRH neurons and the δ subunit–specific agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol was found to activate inward currents in GnRH neurons. Perforated-patch clamp studies showed that 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol exerted the same depolarizing or hyperpolarizing effects as GABA on juvenile and adult GnRH neurons and that tonic GABAA receptor signaling regulates resting membrane potential. Together, these studies reveal the presence of a tonic GABAA receptor current in GnRH neurons that controls their excitability. The level of tonic current is dependent, in part, on neuronal and glial GABA transporter activity and mediated by extrasynaptic δ subunit–containing GABAA receptors.