Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.
Brain, Behavior, and Immunity. 2017-02-01; 60: 240-254
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1. Brain Behav Immun. 2017 Feb;60:240-254. doi: 10.1016/j.bbi.2016.11.010. Epub 2016
Selective dentate gyrus disruption causes memory impairment at the early stage of
experimental multiple sclerosis.
Planche V(1), Panatier A(2), Hiba B(3), Ducourneau EG(2), Raffard G(4),
Dubourdieu N(2), Maitre M(2), Lesté-Lasserre T(2), Brochet B(5), Dousset V(5),
Desmedt A(2), Oliet SH(2), Tourdias T(5).
(1)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: .
(2)INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux,
F-33000 Bordeaux, France.
(3)Univ. Bordeaux, F-33000 Bordeaux, France; CNRS UMR 5287, Institut de
Neurosciences Cognitives et Intégratives d’Aquitaine, F-33000 Bordeaux, France.
(4)Univ. Bordeaux, F-33000 Bordeaux, France; CNRS UMR 5536, Centre de Résonance
Magnétique des Systèmes Biologiques, F-33000 Bordeaux, France.
(5)INSERM, U1215, Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux,
F-33000 Bordeaux, France; CHU de Bordeaux, F-33000 Bordeaux, France.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.