HEREDITARY DEFICIENCIES IN COMPLEMENT C5 ARE ASSOCIATED WITH INTENSIFIED NEURODEGENERATIVE RESPONSES THAT IMPLICATE NEW ROLES FOR THE C-SYSTEM IN NEURONAL AND ASTROCYTIC FUNCTIONS

Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutatio n in the C5 gene. A congenic pair was used: the CS-sufficient (C5(+)) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5(-)) B10.D2/oSnJ w ith the Hc0 allele from the C5-deficient DBA/2J donor strain. In respo nse to the excitotoxin kainic acid (KA), C5(-) mice had more hippocamp al pyramidal neuron death and greater induction of astrocyte mRNAs (GF AP, apoE, apoJ). In primary astrocyte cultures from unlesioned mice, a n inflammatory stimulus (LPS) caused greater production of IL-6 and TN F production in C5(-) mice. These enhanced responses to KA and LPS sug gest that hereditary C5 deficits modify responses to neurodegenerative stimuli of neurons and astrocytes. Moreover, unlesioned C5(-) mice ha d smaller input-output slopes for the NMDA component of the EPSP ampli tude, but enhanced the Ca+2-dependent AMPA binding. Thus, C5 deficits also modify basal properties of glutamatergic neurotransmission that p ertain to synaptic plasticity, These findings are also discussed in re lation to roles of the C-system in Alzheimer disease (AD). C5 deficien cies may also be considered in the choice of strains as transgene host s and for genetic analysis of normal and pathological brain functions. In recent transgenic studies for AD, C5(-) hosts showed greater neuro degeneration, consistent with the present data. These pleiotropic asso ciations of C5 deficiency indicate roles for the C-system in neurodege neration, but also in normal neural functions. (C) 1996 Academic Press , Inc.