Neuronal transport defects of the MAP6 KO mouse - a model of schizophrenia - and alleviation by Epothilone D treatment, as observed using MEMRI.
The MAP6 (microtubule-associated protein 6) KO mouse is a microtubule-deficient model of schizophrenia that exhibits severe behavioral disorders that are associated with synaptic plasticity anomalies. These defects are alleviated not only by neuroleptics, which are the gold standard molecules for the treatment of schizophrenia, but also by Epothilone D (Epo D), which is a microtubule-stabilizing molecule. To compare the neuronal transport between MAP6 KO and wild-type mice and to measure the effect of Epo D treatment on neuronal transport in KO mice, MnCl2 was injected in the primary somatosensory cortex. Then, using manganese-enhanced magnetic resonance imaging (MEMRI), we followed the propagation of Mn(2+) through axonal tracts and brain regions that are connected to the somatosensory cortex. In MAP6 KO mice, the measure of the MRI relative signal intensity over 24h revealed that the Mn(2+) transport rate was affected with a stronger effect on long-range and polysynaptic connections than in short-range and monosynaptic tracts. The chronic treatment of MAP6 KO mice with Epo D strongly increased Mn(2+) propagation within both mono- and polysynaptic connections. Our results clearly indicate an in vivo deficit in neuronal Mn(2+) transport in KO MAP6 mice, which might be due to both axonal transport defects and synaptic transmission impairments. Epo D treatment alleviated the axonal transport defects, and this improvement most likely contributes to the positive effect of Epo D on behavioral defects in KO MAP6 mice.
Inserm U836, Equipe NeuroImagerie Fonctionnelle et Perfusion Cérébrale, BP170, Grenoble 38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France.
Alexia
A
Daoust
Inserm U836, Equipe NeuroImagerie Fonctionnelle et Perfusion Cérébrale, BP170, Grenoble 38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; European Synchrotron Radiation Facility (ESRF), Grenoble, France.
Sylvain
S
Bohic
Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; Inserm U836, Equipe Physiopathologie du Cytosquelette, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives, iRTSV-GPC, Grenoble, France.
Yasmina
Y
Saoudi
Inserm U836, Equipe NeuroImagerie Fonctionnelle et Perfusion Cérébrale, BP170, Grenoble 38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; Bruker Biospin MRI, Ettlingen, Germany.
Clément
C
Debacker
Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; Inserm U836, Equipe Physiopathologie du Cytosquelette, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives, iRTSV-GPC, Grenoble, France.
Sylvie
S
Gory-Fauré
Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; Inserm U836, Equipe Physiopathologie du Cytosquelette, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives, iRTSV-GPC, Grenoble, France.
Annie
A
Andrieux
Inserm U836, Equipe NeuroImagerie Fonctionnelle et Perfusion Cérébrale, BP170, Grenoble 38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France. Electronic address: emmanuel.barbier@ujf-grenoble.fr.
Emmanuel Luc
EL
Barbier
Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; Inserm U836, Equipe Physiopathologie du Cytosquelette, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives, iRTSV-GPC, Grenoble, France. Electronic address: jean-christophe.deloulme@ujf-grenoble.fr.
Jean-Christophe
JC
Deloulme
D000818:Animals; D003287:Contrast Media; D004195:Disease Models, Animal; D034261:Epothilones / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000627:therapeutic use
D003287:Contrast Media; D034261:Epothilones; D008869:Microtubule-Associated Proteins; D050257:Tubulin Modulators; D008345:Manganese
Epothilone D; MAP6; MEMRI; Manganese; Neuronal tract