Astrocytes modulate thalamic sensory processing via mGlu2 receptor activation. (15th July 2017)

• Record Type: Journal Article
• Authors: Copeland, C.S.; Wall, T.M.; Sims, R.E.; Neale, S.A.; Nisenbaum, E.; Parri, H.R.; Salt, T.E.
• Is Part Of: Neuropharmacology. Volume 121(2017)
• Page Start: 100
• Page End: 110
• Publication Date: 2017-07-15
• Subjects: Astrocyte -- Metabotropic glutamate receptor subtype 2 -- Synaptic inhibition -- Thalamus -- Thalamic reticular nucleus; AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- CNQX 6-cyano-7-nitroquinoxaline-2, 3-dione -- DL-APV DL-2-Amino-5-phosphonopentanoic acid -- DMSO dimethyl sulfoxide -- GABA gamma amino butyric acid -- i.p. intraperitoneal -- LY341495 (2S)-2-Amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid -- LY354740 (1S, 2S, 5R, 6S)-2-Aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid -- LY487379 2, 2, 2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)ethanesulfonamide hydrochloride -- mGlu metabotropic glutamate -- mGlu2 metabotropic glutamate receptor subtype 2 -- mGlu3 metabotropic glutamate receptor subtype 3 -- mIPSC miniature inhibitory post-synaptic current -- NaCl sodium chloride -- NIH National Institutes of Health -- NMDA N-methly-d-aspartate -- PAM positive allosteric modulator -- PSTH post-stimulus time histogram -- ROI region of interest -- SEM standard error of the mean -- SR101 Sulforhodamine 101 -- TRN thalamic reticular nucleus -- TTX tetrodotoxin -- VB ventrobasal thalamus; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.04.019
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Astrocytes possess many of the same signalling molecules as neurons. However, the role of astrocytes in information processing, if any, is unknown. Using electrophysiological and imaging methods, we report the first evidence that astrocytes modulate neuronal sensory inhibition in the rodent thalamus. We found that mGlu2 receptor activity reduces inhibitory transmission from the thalamic reticular nucleus to the somatosensory ventrobasal thalamus (VB): mIPSC frequencies in VB slices were reduced by the Group II mGlu receptor agonist LY354740, an effect potentiated by mGlu2 positive allosteric modulator (PAM) LY487379 co-application (30 nM LY354740: 10.0 ± 1.6% reduction; 30 nM LY354740 & 30 μM LY487379: 34.6 ± 5.2% reduction). We then showed activation of mGlu2 receptors on astrocytes: astrocytic intracellular calcium levels were elevated by the Group II agonist, which were further potentiated upon mGlu2 PAM co-application (300 nM LY354740: ratio amplitude 0.016 ± 0.002; 300 nM LY354740 & 30 μM LY487379: ratio amplitude 0.035 ± 0.003). We then demonstrated mGlu2-dependent astrocytic disinhibition of VB neurons in vivo : VB neuronal responses to vibrissae stimulation trains were disinhibited by the Group II agonist and the mGlu2 PAM (LY354740: 156 ± 12% of control; LY487379: 144 ± 10% of control). Presence of the glial inhibitor fluorocitrate abolished the mGlu2 PAM effect (91 ± 5% of control), suggesting the mGlu2 component to the Group II effect can be attributed to activation of mGlu2 receptors localised on astrocytic processes within the VB. Gating of thalamocortical function via astrocyte activation represents a novel sensory processing mechanism. As this thalamocortical circuitry is important in discriminative processes, this demonstrates the importance of astrocytes in synaptic processes underlying attention and cognition. Highlights: Thalamic inhibition is mediated by both neuronal and astrocytic mechanisms. Group II mGlu receptor (mGlu2/3) activation can modulate this thalamic inhibition. Thalamic astrocytes can be activated upon mGlu2 receptor stimulation. This process may enable relevant activity to be discerned from background noise. Targeting astrocytic mGlu2 receptors may therefore affect attention and cognition.