title: Hypocretin (orexin) regulates glutamate input to fast-spiking interneurons in layer V of the Fr2 region of the murine prefrontal cortex.
abstract: We studied the effect of hypocretin 1 (orexin A) in the frontal area 2 (Fr2) of the murine neocortex, implicated in the motivation-dependent goal-directed tasks. In layer V, hypocretin stimulated the spontaneous excitatory postsynaptic currents (EPSCs) on fast-spiking (FS) interneurons. The effect was accompanied by increased frequency of miniature EPSCs, indicating that hypocretin can target the glutamatergic terminals. Moreover, hypocretin stimulated the spontaneous inhibitory postsynaptic currents (IPSCs) on pyramidal neurons, with no effect on miniature IPSCs. This action was prevented by blocking 1) the ionotropic glutamatergic receptors; 2) the hypocretin receptor type 1 (HCRTR-1), with SB-334867. Finally, hypocretin increased the firing frequency in FS cells, and the effect was blocked when the ionotropic glutamate transmission was inhibited. Immunolocalization confirmed that HCRTR-1 is highly expressed in Fr2, particularly in layer V-VI. Conspicuous labeling was observed in pyramidal neuron somata and in VGLUT1+ glutamatergic terminals, but not in VGLUT2+ fibers (mainly thalamocortical afferents). The expression of HCRTR-1 in GABAergic structures was scarce. We conclude that 1) hypocretin regulates glutamate release in Fr2; 2) the effect presents a presynaptic component; 3) the peptide control of FS cells is indirect, and probably mediated by the regulation of glutamatergic input onto these cells.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Aracri
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Banfi
authors.affiliation: Department of Biomolecular Sciences and Biotechnology, University of Milano, Milan 20128, Italy.
authors.forename: Maria Enrica
authors.initials: ME
authors.lastname: Pasini
authors.affiliation: Department of Biomolecular Sciences and Biotechnology, University of Milano, Milan 20128, Italy.
authors.forename: Alida
authors.initials: A
authors.lastname: Amadeo
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Becchetti
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D004594:Electrophysiology / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009287:Naphthyridines; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D046509:Tissue Culture Techniques; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D058468:Receptors, Ionotropic Glutamate; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D014508:Urea
keywords: HCRTR; OXR1; SB-334867; VGLUT; fast-spiking; premotor