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.

[1]  Alan P. Koretsky,et al.  Layer specific tracing of corticocortical and thalamocortical connectivity in the rodent using manganese enhanced MRI , 2009, NeuroImage.

[2]  M. Verhoye,et al.  In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system , 2002, Neuroscience.

[3]  G. Pelled,et al.  NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: Protection against impairments in axonal transport , 2013, Neurobiology of Disease.

[4]  P. Shaw,et al.  Characterization of the caspase cascade in a cell culture model of SOD1‐related familial amyotrophic lateral sclerosis: expression, activation and therapeutic effects of inhibition , 2005, Neuropathology and applied neurobiology.

[5]  C. Delphin,et al.  S100B expression defines a state in which GFAP‐expressing cells lose their neural stem cell potential and acquire a more mature developmental stage , 2007, Glia.

[6]  Nash N. Boutros,et al.  P50 sensory gating ratios in schizophrenics and controls: A review and data analysis , 2008, Psychiatry Research.

[7]  S. Okada,et al.  Manganese Transport in the Neural Circuit of Rat CNS , 1998, Brain Research Bulletin.

[8]  Sandra A G Visser,et al.  Decreased axonal transport rates in the Tg2576 APP transgenic mouse: improvement with the gamma‐secretase inhibitor MRK‐560 as detected by manganese‐enhanced MRI , 2012, The European journal of neuroscience.

[9]  J. Trojanowski,et al.  Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy , 2010, The Journal of Neuroscience.

[10]  I. Gozes,et al.  NAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse—A microtubule-deficient model of schizophrenia , 2010, Peptides.

[11]  Xin Yu,et al.  Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI , 2011, NeuroImage.

[12]  K. Kaibuchi,et al.  DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3ε Complex through Kinesin-1 , 2007, The Journal of Neuroscience.

[13]  J. Ross,et al.  Microtubule-severing enzymes at the cutting edge , 2012, Journal of Cell Science.

[14]  L. Lanfumey,et al.  The deletion of the microtubule‐associated STOP protein affects the serotonergic mouse brain network , 2010, Journal of neurochemistry.

[15]  Alan P. Koretsky,et al.  Tracing Odor-Induced Activation in the Olfactory Bulbs of Mice Using Manganese-Enhanced Magnetic Resonance Imaging , 2002, NeuroImage.

[16]  M. Martres,et al.  Both chronic treatments by epothilone D and fluoxetine increase the short‐term memory and differentially alter the mood status of STOP/MAP6 KO mice , 2012, Journal of neurochemistry.

[17]  J. Costas,et al.  Role of DISC1 Interacting Proteins in Schizophrenia Risk from Genome‐Wide Analysis of Missense SNPs , 2013, Annals of human genetics.

[18]  C. Shaw,et al.  Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. , 2007, Human molecular genetics.

[19]  Richard Paylor,et al.  R‐flurbiprofen improves axonal transport in the Tg2576 mouse model of Alzheimer's Disease as determined by MEMRI , 2011, Magnetic resonance in medicine.

[20]  Han Lin,et al.  Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models. , 2010, Magnetic resonance insights.

[21]  R. Fradley,et al.  STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating , 2005, Behavioural Brain Research.

[22]  Dmitry S. Novikov,et al.  Non-invasive, in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI , 2013, NeuroImage.

[23]  Scott T. Brady,et al.  Neuropathogenic Forms of Huntingtin and Androgen Receptor Inhibit Fast Axonal Transport , 2003, Neuron.

[24]  A. Laquérriere,et al.  Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly , 2010, Acta Neuropathologica.

[25]  Paul Antoine Salin,et al.  The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders. , 2002, Genes & development.

[26]  J. Brunelin,et al.  Reduced Expression of STOP/MAP6 in Mice Leads to Cognitive Deficits , 2012, Schizophrenia bulletin.

[27]  Afonso C. Silva,et al.  In vivo neuronal tract tracing using manganese‐enhanced magnetic resonance imaging , 1998, Magnetic resonance in medicine.

[28]  R. Jacobs,et al.  Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI) , 2007, NeuroImage.

[29]  J. Trojanowski,et al.  The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice , 2012, The Journal of Neuroscience.

[30]  John Bowyer,et al.  Introducing Black-Gold II, a highly soluble gold phosphate complex with several unique advantages for the histochemical localization of myelin , 2008, Brain Research.

[31]  E. Masliah,et al.  Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease , 2005, Science.

[32]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[33]  Xiaowei Zhang,et al.  Deficits in axonal transport in hippocampal-based circuitry and the visual pathway in APP knock-out animals witnessed by manganese enhanced MRI , 2012, NeuroImage.

[34]  M. Martres,et al.  Sustained increase of alpha7 nicotinic receptors and choline-induced improvement of learning deficit in STOP knock-out mice , 2007, Neuropharmacology.

[35]  Hui Zheng,et al.  In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease , 2007, NeuroImage.

[36]  Hiroshi Kita,et al.  Mn and Mg influxes through Ca channels of motor nerve terminals are prevented by verapamil in frogs , 1990, Brain Research.

[37]  R. Pautler In vivo, trans‐synaptic tract‐tracing utilizing manganese‐enhanced magnetic resonance imaging (MEMRI) , 2004, NMR in biomedicine.

[38]  G. Bernardi,et al.  Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats An electron spectroscopy imaging and electron energy-loss spectroscopy study. , 2008, Neurotoxicology.

[39]  M. Suaud-Chagny,et al.  Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice , 2009, Psychopharmacology.

[40]  M. Suaud-Chagny,et al.  Dopaminergic transmission in STOP null mice , 2005, Journal of neurochemistry.

[41]  K. Kaibuchi,et al.  DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  F. Lee,et al.  Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027 , 2012, The Journal of Neuroscience.

[43]  M. Saoud,et al.  The stop null mice model for schizophrenia displays cognitive and social deficits partly alleviated by neuroleptics , 2008, Neuroscience.

[44]  G. Robertson,et al.  Cognitive impairments in the STOP null mouse model of schizophrenia. , 2007, Behavioral neuroscience.

[45]  Paul Antoine Salin,et al.  Microtubule Stabilizer Ameliorates Synaptic Function and Behavior in a Mouse Model for Schizophrenia , 2006, Biological Psychiatry.

[46]  Paul M. Thompson,et al.  Structural and functional neuroimaging phenotypes in dysbindin mutant mice , 2012, NeuroImage.

[47]  A. Esteras-Chopo,et al.  Amyloid toxicity is independent of polypeptide sequence, length and chirality. , 2008, Journal of molecular biology.

[48]  Xiaowei Zhang,et al.  Reward circuitry is perturbed in the absence of the serotonin transporter , 2009, NeuroImage.

[49]  Dirk Wiedermann,et al.  Reproducible imaging of rat corticothalamic pathway by longitudinal manganese-enhanced MRI (L-MEMRI) , 2008, NeuroImage.

[50]  Anna Devor,et al.  In vivo tracing of major rat brain pathways using manganese-enhanced magnetic resonance imaging and three-dimensional digital atlasing , 2003, NeuroImage.

[51]  Raúl San José Estépar,et al.  Diffusion tractography of the fornix in schizophrenia , 2009, Schizophrenia Research.

[52]  N. Logothetis,et al.  Magnetic Resonance Imaging of Neuronal Connections in the Macaque Monkey , 2001, Neuron.

[53]  A. Nehlig,et al.  Hypoglutamatergic activity in the STOP knockout mouse: A potential model for chronic untreated schizophrenia , 2007, Journal of neuroscience research.

[54]  P. Drapeau,et al.  Manganese fluxes and manganese‐dependent neurotransmitter release in presynaptic nerve endings isolated from rat brain. , 1984, The Journal of physiology.

[55]  B. V. van Bon,et al.  Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects , 2012, Journal of Medical Genetics.

[56]  D. Turnbull,et al.  In vivo auditory brain mapping in mice with Mn-enhanced MRI , 2005, Nature Neuroscience.

[57]  E. W. Rubel,et al.  Neuronal tracing with DiI: decalcification, cryosectioning, and photoconversion for light and electron microscopic analysis. , 1990, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[58]  Jieun Kim,et al.  Quantitative in vivo measurement of early axonal transport deficits in a triple transgenic mouse model of Alzheimer's disease using manganese-enhanced MRI , 2011, NeuroImage.