Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors. (May 2015)

• Record Type: Journal Article
• Authors: Copeland, C.S.; Neale, S.A.; Salt, T.E.
• Is Part Of: Neuropharmacology. Volume 92(2015)
• Page Start: 16
• Page End: 24
• Publication Date: 2015-05
• Subjects: Mediodorsal thalamus -- Metabotropic glutamate receptor -- Synaptic inhibition -- Burst firing -- Schizophrenia; DMSO dimethyl sulfoxide -- GABA gamma-amino butyric acid -- i.p. intraperitoneal -- 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 -- MD mediodorsal thalamus -- mGlu metabotropic glutamate -- mGlu2 metabotropic glutamate subtype 2 -- mGlu3 metabotropic glutamate subtype 3 -- NaCl sodium chloride -- NMDA N-methyl d-aspartate -- PAM positive allosteric modulator -- PFC prefrontal cortex -- PSTH post-stimulus time histogram -- TRN thalamic reticular nucleus -- VB ventrobasal thalamus; N-Methylaspartate (PubChem CID 22880) -- Egluetad (PubChem CID 156665) -- N-(4-(2-methoxyphenoxy)phenyl)-N-(2, 2, 2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (PubChem CID 9825084); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2014.12.031
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia. Highlights: There is heterogeneity in Group II receptor physiology across thalamic nuclei. This differential distribution may facilitate multimodal thalamic nuclei functions. Group II receptor activation reduced burst firing via reducing thalamic inhibition. Increased thalamic inhibition precipitates impairments in cognitive function. Activating the Group II receptors may therefore enhance cognitive function.