title: Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors.
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.
authors.affiliation: Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK. Electronic address: carolinecopeland@gmail.com.
authors.forename: C S
authors.initials: CS
authors.lastname: Copeland
authors.affiliation: Neurexpert Ltd, Kemp House, City Road, London, EC1V 2NX, UK. Electronic address: stuartneale@neurexpert.com.
authors.forename: S A
authors.initials: SA
authors.lastname: Neale
authors.affiliation: Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK. Electronic address: t.salt@ucl.ac.uk.
authors.forename: T E
authors.initials: TE
authors.lastname: Salt
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001703:Biophysics; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D007478:Iontophoresis; D008297:Male; D020645:Mediodorsal Thalamic Nucleus / Q000166:cytology*; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014738:Vibrissae / Q000294:innervation; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018683:Excitatory Amino Acid Agents; D018094:Receptors, Metabotropic Glutamate; D005680:gamma-Aminobutyric Acid
keywords: Burst firing; Egluetad (PubChem CID 156665); Mediodorsal thalamus; Metabotropic glutamate receptor; N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (PubChem CID 9825084); N-Methylaspartate (PubChem CID 22880); Schizophrenia; Synaptic inhibition