Thyrotropin‐releasing hormone increases GABA release in rat hippocampus

Abstract

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 GABA A 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 Ba 2+ 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 Gα q/11 , but were independent of its known downstream effectors, a direct coupling may exist between Gα q/11 and K + channels. Inhibition of the function of dynamin slowed the desensitization of TRH responses. TRH inhibited seizure activity induced by Mg 2+ 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.

Excitation of Histaminergic Tuberomamillary Neurons by Thyrotropin-Releasing Hormone

“…At 50 M CDZ, a concentration used also in previous studies for the blockade of TRH receptors (Deng et al, 2006), the TRH effect was abolished (n ϭ 6; p ϭ 0.0005; Mann-Whitney U test) (Fig. 1 D).…”

“…Although we tried to use maximal concentrations of TRH known to be within 0.5-10 M (Deng et al, 2006) in our initial sharp electrode recordings, 10 M of TRH caused suppression of firing and irreversible depolarization in some of TMN neurons. Therefore, we selected for all aforementioned experiments a TRH concentration of 1.5 M. Construction of complete dose-response curve for TRH was not possible for the following reasons: first, TRH could be applied only once to a single slice, and different cells recorded from different slices showed considerable variation in the TRH response magnitude; second, the number of responding cells was Ͻ50% with concentrations of TRH Յ1 M. The TRHdegrading enzyme is strongly expressed in the hypothalamus (Heuer et al, 2000), making the real concentration at the recording site (within 450-m-thick slice) after bath delivery of TRH unpredictable in each single case.…”

“…TRH analogues are also known as antiepileptics in animal seizure models (Nillni and Sevarino, 1999) and in clinical use (Kubek and Garg, 2002). Although the antiepileptic function of TRH can be explained by its excitatory action on hippocampal interneurons (Atzori and Nistri, 1996;Deng et al, 2006), cellular mechanisms underlying the promotion of arousal are not fully elucidated. Broberger and McCormick (2005) demonstrated a depolarization of perigeniculate and thalamocortical cells in the lateral geniculate nucleus by TRH and a transformation of perigeniculate neurons from bursting to the tonic, single-spike mode of action potential generation.…”

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…Furthermore, the hippocampal release of TRH by seizures has also been reported [300]. In turn, TRH inhibits glutamate release but increases GABA release in the hippocampus [301,302], which might be the basis of its antiepileptic action.…”

Tyreoliberin (Trh) – The Regulatory Neuropeptide of Cns Homeostasis

“…During acute injury of neuronal tissue, TRH could influence on release of glutamate, GABA, acetylcholine, endogenous opioids or leukotriens and restore an energetic status of cells which was affected during injury [12,17,35,37]. Recently there has been very interesting data released, that points to receptor independent, intracellular mechanisms of the TRH neuroprotective action.…”