title: Interferon-β1a modulates glutamate neurotransmission in the CNS through CaMKII and GluN2A-containing NMDA receptors.
abstract: Interferons (IFNs) are widely expressed cytokines with antiviral and immune-modulating effects and have been utilised for the treatment of several human pathological conditions. In particular, the immune-modulatory drug IFN-β is utilized in the treatment of multiple sclerosis (MS), a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS). Although the effects of IFN-β on immune cells functions have been widely investigated, information about the ability of the drug to modulate neuronal transmission in the CNS is still largely lacking. The aim of this study was to investigate the ability of IFN-β1a to modulate excitatory synaptic transmission in the CNS. Whole cell patch-clamp electrophysiological recordings were performed in the nucleus striatum, one of the CNS grey matter structures that is prone to degenerate during the course of MS. We demonstrate that the drug IFN-β1a, independently from its known peripheral immune-modulating action, is able to directly modulate synaptic transmission. In particular, we demonstrated that IFN-β1a reduces the amplitude of striatal excitatory post-synaptic currents, indicating an inhibitory effect on glutamate neurotransmission, and in particular on its NMDA component. The inhibitory effect of IFN-β1a on striatal glutamate neurotransmission was found to be mediated by a novel post-synaptic mechanism requiring Ca(2+), CaMKII and the GluN2A subunit of the NMDA receptor, without the involvement of the classic STAT1 pathway. The evidence of a novel neuro-modulating effect of IFN-β shed light on the mechanisms of action of the drug and on the complex bidirectional interaction occurring between the immune and the nervous system. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy. Electronic address: massimiliano.difilippo@unipg.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Sezione di Fisiologia e Biochimica, Dipartimento di Medicina Sperimentale, Università Degli Studi di Perugia, Perugia, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Arcangeli
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Durante
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Di Gregorio
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università Degli Studi di Milano, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università Degli Studi di Perugia, Ospedale Santa Maria Della Misericordia, Perugia, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D018698:Glutamic Acid / Q000502:physiology*; D016899:Interferon-beta / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018698:Glutamic Acid; D016899:Interferon-beta; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Glutamate; Interferon; Multiple sclerosis; NMDA; Neurotransmission