Thyrotropin-releasing hormone increases GABA release in rat hippocampus.
Thyrotropin-releasing hormone (TRH) is a tripeptide that is widely distributed in the brain including the hippocampus where TRH receptors are also expressed. TRH has anti-epileptic effects and regulates arousal, sleep, cognition, locomotion and mood. However, the cellular mechanisms underlying such effects remain to be determined. We examined the effects of TRH on GABAergic transmission in the hippocampus and found that TRH increased the frequency of GABAA receptor-mediated spontaneous IPSCs in each region of the hippocampus but had no effects on miniature IPSCs or evoked IPSCs. TRH increased the action potential firing frequency recorded from GABAergic interneurons in CA1 stratum radiatum and induced membrane depolarization suggesting that TRH increases the excitability of interneurons to facilitate GABA release. TRH-induced inward current had a reversal potential close to the K+ reversal potential suggesting that TRH inhibits resting K+ channels. The involved K+ channels were sensitive to Ba2+ but resistant to other classical K+ channel blockers, suggesting that TRH inhibits the two-pore domain K+ channels. Because the effects of TRH were mediated via Galphaq/11, but were independent of its known downstream effectors, a direct coupling may exist between Galphaq/11 and K+ channels. Inhibition of the function of dynamin slowed the desensitization of TRH responses. TRH inhibited seizure activity induced by Mg2+ deprivation, but not that generated by picrotoxin, suggesting that TRH-mediated increase in GABA release contributes to its anti-epileptic effects. Our results demonstrate a novel mechanism to explain some of the hippocampal actions of TRH.
Deng
Pan-Yue
PY
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
Porter
James E
JE
Shin
Hee-Sup
HS
Lei
Saobo
S
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D034281:Dynamins / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta; D011188:Potassium / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D007527:Isoenzymes; D024683:Potassium Channels, Tandem Pore Domain; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D013973:Thyrotropin-Releasing Hormone; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D034281:Dynamins; D011188:Potassium