Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha

Cytokines belonging to the type I interferon (e.g. interferon-alpha) family are important in the host response to infection and may have complex and b road ranging actions in the central nervous system (CNS) that may be benefi cial or harmful. To better understand the impact of the CNS expression of t he type I interferons (IFN), transgenic mice were developed that produce IF N-alpha(1) chronically from astrocytes. In two independent transgenic lines with moderate and low levels of astrocyte IFN-alpha mRNA expression respec tively, a spectrum of transgene dose- and age-dependent structural and func tional neurological alterations are induced. Structural changes include neu rodegeneration with loss of cholinergic neurons, gliosis, angiopathy with m ononuclear cell cuffing, progressive calcification affecting basal ganglia and cerebellum and the up-regulation of a number of IFN-alpha-regulated gen es. At a functional level, in vivo and in vitro electrophysiological studie s revealed impaired neuronal function and disturbed synaptic plasticity wit h pronounced hippocampal hyperexcitability. Severe behavioral alterations w ere also evident in higher expressor GFAP-IFN alpha mice which developed fa tal seizures around 13 weeks of age precluding their further behavioral ass essment. Modest impairments in discrimination learning were measured in low er expressor GFAP-IFN alpha mice at various ages (7-42 weeks). The behavior al and electrophysiological findings suggest regional changes in hippocampa l excitability which may be linked to abnormal calcium metabolism and loss of cholinergic neurons in the GIFN mice. Thus, these transgenic mice provid e a novel animal model in which to further evaluate the mechanisms that und erlie the diverse actions of type I interferons in the intact CNS and to li nk specific structural changes with functional impairments. (C) 1999 Elsevi er Science B.V. All rights reserved.