Characterisation of spinal cord in a mouse model of spastic paraplegia related to abnormal axono-myelin interactions by in vivo quantitative MRI.

International audienceIn inherited neurodegenerative disorders the engineering of genetically modified mice for the causative genes have provided new insights in the understanding of axono-glial interactions. Patients lacking the major proteins of the central nervous system myelin, the proteolipoproteins (PLP1) exhibit an ascending axonopathy, named spastic paraplegia type 2. Our objective was to examine the interest of using quantitative MRI for non invasive detection of spinal cord (SC) consequences of the PLP1 defect in a mouse model of SPG2 (PLP1-/Y). For this purpose an MRI acquisition and retrospective correction chain was set up to map apparent diffusion coefficients (ADC) and T2 in the mouse cervical SC which improve the intra- and inter-animal homogeneity. This reliable imaging processing protocol allowed to detect significant changes between PLP1-/Y and wild type 15-month old SC, mainly no longer detected ex vivo after SC fixation. On the basis of ADC(//) and ADC( perpendicular) variations, white matter (WM) damages were characterised on both the myelin and axonal components. The microstructural changes observed in the Plp1 deficient grey matter (GM) were concomitantly related to the isotropic increase of GM ADC. The T2 reduction measured in the WM as well as the GM of the mutant SC seems to be also an interesting marker of the SC axono-glial dysfunction. The present study demonstrated the interest of quantitative MRI for phenotyping in vivo the WM and GM changes in SC neurodegenerative disorders related to myelin and impaired glia-axonal interaction

Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice

The possible role of the CB2 receptor (CB2 r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB 2 r in the regulation of such behaviors. Mice lacking the CB 2 r (CB2 KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D2 (D2 r), adrenergic-α 2C (α 2C r), serotonergic 5-HT 2A and 5-HT 2C receptors (5-HT 2A r and 5-HT 2C r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB 2 r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it normalized the PPI deficit in CB2 KO mice. CB2 KO mice presented increased D2 r and α 2C r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT 2C r gene expression in the dorsal raphe (DR), and 5-HT 2A r gene expression in the PFC. Chronic risperidone treatment in WT mice left α 2C r gene expression unchanged, decreased D2 r gene expression (15 g/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB2 KO, the gene expression of D2 r in the PFC, of α 2C r in the LC, and of 5-HT 2C r and 5-HT 2Ar in PFC was reduced; 5-HT 2C r and 5-HT 2A r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB2 r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB2 r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders. © 2011 American College of Neuropsychopharmacology. All rights reserved.This research was supported by grants from the Ministry of Science and Innovation (SAF 2008-01106) and Ministry of Health (RETICS RD06/0001/1004 and PNSD 2007/061) to JM. AOA is a postdoctoral fellow of ‘Fundación para la Investigación Sanitaria en Castilla La Mancha’ (FISCAM).Peer Reviewe