Accelerated development of neurochemical and behavioral deficits in LP-BM5infected mice with targeted deletions of the IFN-gamma gene

Mice homozygous for a germline deletion of the interferon-gamma gene (IFN-g amma (-/-)) were infected with the LP-BM5 (BM5) retrovirus mixture to deter mine if the inability to produce IFN-gamma reduces collateral CNS damage as sociated with chronic neuroinflammation. Virus burdens in spleens and brain s of infected mice were comparable, but spatial memory deficits were manife sted earlier and to a greater extent in BMS/IFN-gamma (-/-) mice. The mice with spatial memory deficits showed considerable degradation of axone and m icrotubules, along with apoptosis of striatal neurons. These lesions were a ccompanied by extensive infiltration of perivascular spaces and ventricles by iNOS-positive leukocytes, and a 17-fold increase in CSF glutamate levels . Despite high levels of VCAM and ICAM expression on cerebral vasculature e ndothelia, the serum levels of soluble ICAM-1 were significantly decreased in BM5/IFN-gamma (-/-) mice, which may contribute to the enhanced leukocyte infiltration and subsequent neuronal damage. These results suggest that th e presence of IFN-gamma is necessary at some points in the inflammatory pro cess to protect against neurodegeneration. (C) 2000 Elsevier Science B.V. A ll rights reserved.