Desipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling

Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CM field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-positive cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Tricyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biological underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyse a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favoured an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the molecular and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clinical use of DMI. (C) 2016 Elsevier Ltd. All rights reserved

Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments

Abstract Background: The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined. Methods: The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels. Results: Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at −133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from −98.8 ± 1.6 to −108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2−/− mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo. Conclusions: Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon. </jats:sec

Propofol and Sevoflurane Differentially Modulate Cortical Depolarization following Electric Stimulation of the Ventrobasal Thalamus

The neuronal mechanisms how anesthetics lead to loss of consciousness are unclear. Thalamocortical interactions are crucially involved in conscious perception; hence the thalamocortical network might be a promising target for anesthetic modulation of neuronal information pertaining to arousal and waking behavior. General anesthetics affect the neurophysiology of the thalamus and the cortex but the exact mechanisms of how anesthetics interfere with processing thalamocortical information remain to be elucidated. Here we investigated the effect of the anesthetic agents sevoflurane and propofol on thalamocortical network activity in vitro. We used voltage-sensitive dye imaging techniques to analyze the cortical depolarization in response to stimulation of the thalamic ventrobasal nucleus in brain slices from mice. Exposure to sevoflurane globally decreased cortical depolarization in a dose-dependent manner. Sevoflurane reduced the intensity and extent of cortical depolarization and delayed thalamocortical signal propagation. In contrast, propofol neither affected area nor amplitude of cortical depolarization. However, propofol exposure resulted in regional changes in spatial distribution of maximum fluorescence intensity in deep regions of the cortex. In summary, our experiments revealed substance-specific effects on the thalamocortical network. Functional changes of the neuronal network are known to be pivotally involved in the anesthetic-induced loss of consciousness. Our findings provide further evidence that the mechanisms of anesthetic-mediated loss of consciousness are drug- and pathway-specific