title: Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator.
abstract: Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multi-electrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit.
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Pollard
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Toledo, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Bartolome
authors.affiliation: Department of Pharmacology, and the Vanderbilt Center for Neuroscience Drug Discovery 2, Vanderbilt University Medical School, Nashville, TN, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium hshaban@its.jnj.com.
authors.forename: Hamdy
authors.initials: H
authors.lastname: Shaban
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D001549:Benzamides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C000598420:N-(1,3-diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide; D011720:Pyrazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; D008734:Methoxyhydroxyphenylglycol; D002217:Carbachol; C010117:3,4-dihydroxyphenylglycol
keywords: Cholinergic transmission; inhibitory postsynaptic currents; metabotropic glutamate receptors; multi-electrode recordings; positive allosteric modulator