Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone.

The histaminergic tuberomamillary nucleus (TMN) controls arousal and attention, and the firing of TMN neurons is state-dependent, active during waking, silent during sleep. Thyrotropin-releasing hormone (TRH) promotes arousal and combats sleepiness associated with narcolepsy. Single-cell reverse-transcription-PCR demonstrated variable expression of the two known TRH receptors in the majority of TMN neurons. TRH increased the firing rate of most (ca 70%) TMN neurons. This excitation was abolished by the TRH receptor antagonist chlordiazepoxide (CDZ; 50 mum). In the presence of tetrodotoxin (TTX), TRH depolarized TMN neurons without obvious change of their input resistance. This effect reversed at the potential typical for nonselective cation channels. The potassium channel blockers barium and cesium did not influence the TRH-induced depolarization. TRH effects were antagonized by inhibitors of the Na(+)/Ca(2+) exchanger, KB-R7943 and benzamil. The frequency of GABAergic spontaneous IPSCs was either increased (TTX-insensitive) or decreased [TTX-sensitive spontaneous IPSCs (sIPSCs)] by TRH, indicating a heterogeneous modulation of GABAergic inputs by TRH. Facilitation but not depression of sIPSC frequency by TRH was missing in the presence of the kappa-opioid receptor antagonist nor-binaltorphimine. Montirelin (TRH analog, 1 mg/kg, i.p.) induced waking in wild-type mice but not in histidine decarboxylase knock-out mice lacking histamine. Inhibition of histamine synthesis by (S)-alpha-fluoromethylhistidine blocked the arousal effect of montirelin in wild-type mice. We conclude that direct receptor-mediated excitation of rodent TMN neurons by TRH demands activation of nonselective cation channels as well as electrogenic Na(+)/Ca(2+) exchange. Our findings indicate a key role of the brain histamine system in TRH-induced arousal.

Glutamine-induced membrane currents in cultured rat hippocampal neurons.

Glutamine is present at high concentrations in the extracellular fluid of the brain. It shuttles between glia cells and neurons, and serves as a precursor for both glutamate and gamma-amino butyric acid. Direct actions of glutamine at central neurons are, however, not well understood. Here we showed that L-glutamine (0.5-10 mm) evoked a dose-dependent inward transmembrane current in primarily cultured rat hippocampal neurons. Typical responses were outwardly rectifying and had a reversal potential around 0 mV. The current was partially sensitive towards blockers of ionotropic glutamate receptors and was partially carried by activation of N-methyl-D-aspartate receptors. However, cellular responses to L-glutamine showed clear biophysical and pharmacological differences to L-glutamate-evoked currents. Responses were highly specific for L-glutamine and no responses could be evoked by D-glutamine, L-alanine, L-valine, L-leucine and the system-A-specific agonist alpha-(methylamino)-isobutyric acid. Together, these data indicate that hippocampal neurons can be depolarized by electrogenic effects specific for L-glutamine.

Presynaptic ionotropic GABA receptors.

Following the classical work on presynaptic inhibition in the spinal cord, recent work has revealed an astonishing abundance and diversity of presynaptic ionotropic GABA receptors. While modern techniques allow for detailed studies at the cellular and molecular level in almost all regions of the CNS, our understanding of the function of such receptors is still far from complete. One major shortcoming is the lack of knowledge regarding chloride concentration inside axons or axon terminals. Therefore, the voltage change upon activation of presynaptic GABA receptors is difficult to predict. Moreover, even if the presynaptic potential transient was known, it turns out difficult to predict the effects on presynaptic function, which may be differentially influenced by various mechanisms, including activation or inactivation of voltage-gated ion channels and shunt effects. This review summarizes several key examples of presynaptic ionotropic GABA receptors and outlines the possible mechanisms that have to be kept in mind when unravelling this potentially important mechanism of synaptic signalling and plasticity.