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• W2103108446 abstract "Thalamocortical (TC) neurons, including those of the dorsal lateral geniculate nucleus (dLGN), one of the visual sensory thalamic nuclei, exhibit two forms of GABAA receptor-mediated inhibition: phasic or classical inhibitory postsynaptic currents (IPSCs) generated by the activation of synaptic GABAA receptors (sGABAAR) and tonic inhibition generated by extra- or peri-synaptic GABAA receptors (eGABAAR) 1, 2. The source of GABA mediating tonic inhibition mostly arises from spillover out of the synaptic cleft, because tonic inhibition is blocked by TTX and removal of extracellular Ca2+ in adult murine dLGN TC neurons 3. Therefore, modulation of vesicular GABA release may not only affect phasic but also tonic inhibition 1, 4. Previous work in the cat and rat dLGN has shown that several neurotransmitters, including acetylcholine, serotonin (5-HT), dopamine, and norepinephrine can modulate vesicular GABA release from inhibitory interneurons, resulting in changes in phasic inhibition (IPSC frequency), primarily through presynaptic modulation of GABA release from dendro-dendritic synapses 5. However, except for dopamine in the somatosensory thalamus, the effect of these neurotransmitters on tonic GABAA inhibition in TC neurons has not been examined. Here, we investigated whether 5-HT and its 5-HT1A, 5-HT2A and 5-HT2C receptors exert a control over tonic and phasic GABAA currents in dLGN TC neurons. We used whole cell patch clamp recordings in coronal slices (300 mm) containing the dLGN from postnatal day 20–25 Wistar rats. Data analysis and experimental procedures were similar to those previously described 1, 6 and in accordance with the Animals (Scientific Procedures) Act 1986 (UK). Focal application of gabazine (GBZ, 100 mM) was used to reveal the presence of tonic GABAA current (Figure 1). All serotonergic drugs were dissolved in the recording solution, and their concentrations, co-administration, and effects on phasic and tonic GABAA current are shown in Table 1 and Figure 1. We found that 5-HT enhances phasic GABAA inhibition (i.e., spontaneous IPSCs), but has no action on tonic inhibition. These effects are identical to those observed following 5-HT1A/7R activation with 8-OH-DPAT. On the other hand, α-M-5-HT and mCPP enhances and reduces, respectively, both phasic and tonic GABAA inhibition. These effects are dependent on 5-HT2AR and 5-HT2CR activation, respectively, as they are blocked by co-perfusion with selective antagonists, ketanserin, and SB242084. Thus, the lack of 5-HT modulation of tonic inhibition might be explained by the counterbalance of co-activation of 5-HT2ARs and 5-HT2CRs by the endogenous ligand (Figure 1 and Table 1). Our findings are in agreement with recent evidence in visual cortex showing that 5-HT enhances phasic inhibition by activating 5-HT2ARs (via calcium/calmodulin-dependent protein kinase II, CaMKII) 7. However, whereas in visual cortex 5-HT decreases tonic inhibition via a 5-HT1AR-dependent suppression of protein kinase A (PKA) activity) 7, we could not detect any effect on the tonic current by 5-HT or 5-HT1A/7R activation in the dLGN. Moreover, our study is in agreement with previous in vivo studies in which stimulation of the dorsal raphe nucleus decreased TC neuron firing in the dLGN 8, suggesting 5-HT had an inhibitory action. In contrast, however, in vitro intracellular recordings of ferret TC cells found that 5-HT is predominantly hyperpolarizing in all thalamic nuclei tested except for the dLGN, medial geniculate and in a subset of pulvinar neurons, in which depolarizing responses were observed 9. More recently, it has been shown that in rats 5-HT excites all TC neurons in first-order thalamic nuclei and most (85%) TC neurons in higher order nuclei, while it hyperpolarizes the remaining cells 10. Specifically in the rat dLGN, 5-HT2CR activation with α-M-5-HT and the highly selective ligand CP-809,101 produced depolarization of TC neurons shifting their firing from bursts to tonic 11. This would suggest that serotonin has a complex modulatory effect on thalamic nuclei which appear to be nucleus-, 5-HTR subtype-, and 5-HTR synaptic localization-dependent. 5-HT1A/7 are present in the thalamus 12, and whereas a strong 5-HT2CR immunoreactivity has been detected, although not somatically, in dLGN TC neurons 13, 5-HT2AR immunostaining did not reach detectable levels 11. Interestingly, both 5-HT2AR and 5-HT2CR mRNA are expressed in the dLGN GABAergic interneurons of young rats 14. Therefore, it is likely that the increase in sIPSC frequency that we observed in our study may result from postsynaptic 5-HT2Rs on dendritic F2 terminals of dLGN interneurons, as previously shown 14. Nevertheless, 5-HT1A/7R and 5-HT2A/2CRs might also be located postsynaptically on TC neurons, and their activation may lead to phosphorylation of different subunits of sGABAARs and eGABAARs acting to differentially modulate their function. The binding of 5-HT to 5-HT1A/7R and 5-HT2A/2CRs might activate multiple signal transduction cascades, which ultimately activate different protein kinases, such as PKA or protein kinase C (PKC) and differently regulate sGABAARs and eGABAARs, as indicated by our results. On the other hand, the potential contribution of 5-HTRs on retinal and cortical terminals can be ruled out as glutamatergic function was blocked in our preparations through the addition of kynurenic acid to the recording solution. Overall, this study is the first to show a modulation of tonic GABAA current by 5-HTRs in the thalamus and also to highlight that phasic and tonic inhibition in the dLGN are modulated by 5-HT through different receptor subtypes, leading to a finely tuned balance of sensory information processing in the dLGN. By showing a differential modulation of phasic versus tonic GABAA inhibition, our results demonstrate a novel mechanism by which the ascending serotonergic afferents can control the thalamic gate to the visual cortex in a behavioral state-dependent manner. Moreover, because of the putative role for thalamic tonic GABAA inhibition in sleep regulation and pathological oscillations, such as those present in absence epilepsy, the opposing effects of 5-HT2ARs and 5-HT2CRs activation may provide suitable targets for pharmacological intervention in sleep and other CNS disorders. Epilepsy Research UK (grant P1202 to VC and GDG), The Welcome Trust (grant 91882 to VC), and the Malta Council of Science and Technology (grant R&I-2013-14 to GDG and VC). The authors declare no conflict of interest." @default.
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• W2103108446 date "2015-11-11" @default.
• W2103108446 modified "2023-09-27" @default.
• W2103108446 title "Differential Control by 5-HT and 5-HT1A, 2A, 2C Receptors of Phasic and Tonic GABAA Inhibition in the Visual Thalamus" @default.
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• W2103108446 doi "https://doi.org/10.1111/cns.12480" @default.
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