RESUMEN
We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3 min. The prolongation of hypoxic periods to 6 min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6 min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3.
Asunto(s)
Región CA3 Hipocampal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Hipoxia/fisiopatología , Red Nerviosa/fisiología , Células Piramidales/fisiología , Adenosina/metabolismo , Antagonistas del Receptor de Adenosina A1/farmacología , Animales , Bicuculina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Antagonistas de Receptores de GABA-A/farmacología , Técnicas In Vitro , Red Nerviosa/efectos de los fármacos , Oxígeno/metabolismo , Técnicas de Placa-Clamp , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Valina/análogos & derivados , Valina/farmacología , Xantinas/farmacologíaRESUMEN
Agents such as sertindole and astemizole affect heart action by inducing long-QT syndrome, suggesting that apart from their neuronal actions through histamine receptors, 5-HT2 serotonin receptors and D2 dopamine receptors they also affect ether-a-go-go channels and particularly ether-a-go-go-related (ERG) potassium (K(+)) channels, comprising the K(v) 11.1, K(v) 11.2 and K(v) 11.3 voltage-gated potassium currents. Changes in ERG K(+) channel expression and activity have been reported and may be linked to schizophrenia [Huffaker, S.J., Chen, J., Nicodemus, K.K., Sambataro, F., Yang, F., Mattay, V., Lipska, B.K., Hyde, T.M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., Proust, M.J., Soghoyan, A., Caforio, G., Callicott, J.H., Bertolino, A., Meyer-Lindenberg, A., Chang, J., Ji, Y., Egan, M.F., Goldberg, T.E., Kleinman, J.E., Lu, B. & Weinberger DR. (2009). Nat. Med., 15, 509-518; Shepard, P.D., Canavier, C.C. & Levitan, E.S. (2007). Schizophr Bull., 33, 1263-1269]. We have previously shown that histamine H1 blockers augment gamma oscillations (γ) which are thought to be involved in cognition and storage of information. These effects were particularly pronounced for γ induced by acetylcholine. Here we have compared neuronal effects of three agents which interfere with ERG K(+) channels. We found that astemizole and sertindole, but not the K(v) 11 channel blocker E4031, augmented γ induced by acetylcholine in hippocampal slices. Kainate-induced γ were only affected by astemizole. Evoked responses induced by stratum radiatum stimulation in area CA1 revealed that only E4031 augmented stimulus-induced synaptic potentials and neuronal excitability. Our findings suggest that K(v) 11 channels are involved in neuronal excitability without clear effects on γ and that the effect of astemizole is related to actions on H1 receptors.
Asunto(s)
Ondas Encefálicas/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Acetilcolina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Astemizol/farmacología , Imidazoles/farmacología , Indoles/farmacología , Ácido Kaínico/farmacología , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar , Potenciales Sinápticos/efectos de los fármacosRESUMEN
Hypoxia or global ischemia causes rapid loss of consciousness and a sudden increase in spontaneous transmitter release suggesting that coordinated synaptic activity is impaired. Gamma oscillations (30-100 Hz) are thought to provide for binding of parallel processed information in the brain, contributing to cognition and formation of short-term memory. We hypothesized that gamma-oscillations are rapidly blocked by hypoxia and that prolonged hypoxia reduces the capability to generate such activity. In ventral hippocampal slices, kainate-induced gamma-oscillations reversibly declined 40 s after onset of 3 min hypoxia. Repetition of such hypoxic periods led to accumulative impairment of gamma-activities. By contrast, 6 min of hypoxia led to a transient anoxic depolarization after which gamma-oscillations remained almost completely blocked.
Asunto(s)
Electroencefalografía/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipoxia Encefálica/fisiopatología , Ácido Kaínico/farmacología , Animales , Interpretación Estadística de Datos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Células Piramidales/fisiología , Ratas , Ratas WistarRESUMEN
We investigated the interaction between ambient histamine and acetylcholine by studying γ oscillations in rat hippocampus, induced by bath application of acetylcholine (10 µM combined with 2 µM physostigmine). The power of γ was significantly increased by the H1 antagonist, fexofenadine, and H2 receptor agonist, dimaprit, and reduced by the H2 receptor antagonist, cimetidine. These effects suggest an interference with ambient histamine. Depletion of histamine from their fibers by hypoxia and blockade of histamine uptake resulted in loss of the fexofenadine-mediated and cimetidine-mediated effects on acetylcholine-induced γ. We conclude that acetylcholine can cause histamine release from histaminergic fibers and thereby can influence attentional states by augmenting γ. This effect is likely due to activation of H2 receptors by histamine and thereby might contribute to the previously described enhancement of working memory.