title: Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.
abstract: Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France; CHU de Clermont-Ferrand, F-63000 Clermont-Ferrand, France. Electronic address: planche.vincent@gmail.com.
authors.forename: Vincent
authors.initials: V
authors.lastname: Planche
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Panatier
authors.affiliation: Univ. Bordeaux, F-33000 Bordeaux, France; CNRS UMR 5287, Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, F-33000 Bordeaux, France.
authors.forename: Bassem
authors.initials: B
authors.lastname: Hiba
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Eva-Gunnel
authors.initials: EG
authors.lastname: Ducourneau
authors.affiliation: Univ. Bordeaux, F-33000 Bordeaux, France; CNRS UMR 5536, Centre de Résonance Magnétique des Systèmes Biologiques, F-33000 Bordeaux, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Raffard
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Dubourdieu
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Maitre
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lesté-Lasserre
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France; CHU de Bordeaux, F-33000 Bordeaux, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brochet
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France; CHU de Bordeaux, F-33000 Bordeaux, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dousset
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Desmedt
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France.
authors.forename: Stéphane H
authors.initials: SH
authors.lastname: Oliet
authors.affiliation: INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33000 Bordeaux, France; CHU de Bordeaux, F-33000 Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tourdias
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D017774:Long-Term Potentiation / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009103:Multiple Sclerosis / Q000150:complications*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
keywords: Dentate gyrus; Diffusion tensor imaging; Experimental autoimmune encephalomyelitis; Hippocampus; Memory impairment; Microglia; Multiple sclerosis; Synaptic plasticity