Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 Positive allosteric modulator

Marie Pollard, Jose Manuel Bartolome, P. Jeffrey Conn, Thomas Steckler, Hamdy Shaban

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 fearconditioned 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 multielectrode 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.

Original languageEnglish
Pages (from-to)935-946
Number of pages12
JournalJournal of Psychopharmacology
Volume28
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

Keywords

  • Cholinergic transmission
  • Inhibitory postsynaptic currents
  • Metabotropic glutamate receptors
  • Multi-electrode recordings
  • Positive allosteric modulator

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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