PRENATAL HUMAN INFLUENZA
VIRAL INFECTION IN MICE DECREASES THE EXPRESSION OF REELIN IN THE
NEONATAL CORTEX AND HIPPOCAMPUS
S.H. Fatemi, E-S
Emamian, D. Kist, R.W. Sidwell, P. Akhter, S. Sheikh, a. Shier,
and K. Bailey. Department of Psychiatry, Cell Biology and
Neuroanatomy, Division of Neuroscience Research, University of
Minnesota, Minneapolis, MN, U.S.A. and Institute for Antiviral
Research, Utah State University, Logan, UT, U.S.A.
Reelin is a 385 Kda secretory protein
which is synthesized and secreted by Cajal-Retzius cells in the
developing mouse brain and is responsible for correct temporal
lamination of the central nervous system. Reelin mutant mice
exhibit abnormal positioning of neurons in the cerebrum,
cerebellum and hippocampus. A recent report indicated a 40%
decrease in reelin mRNA in brains of patients with schizophrenia.
Recent reports indicate an association between maternal second
trimester viral infection and later development of schizophrenia.
We hypothesized that 2nd trimester human influenza
infection in day 9 pregnant mice would alter the expression of
reelin in day 0 neonatal brains. Intranasal infection of day 9
pregnant C57BL6 mice with 10-5 dilution of human
influenza virus HINI caused sublethal infection in pregnant
animals. Day 0 neonatal brains from infected and sham infected
groups were fixed in 4% paraformaldehyde and cryopreserved in
sucrose. Silver-enhanced 5 nm gold conjugated probe
immunocytochemical localization of Cajal-Retzius cells containing
reelin was accomplished using specific monoclonal antibody
against mouse reelin. Reelin positive cells were identified and
counted in layer I of the neocortex and the hippocampus and in
the cortical and hippocampal layers II-VI and white matter.
Results show a significant reduction in the number of reelin
positive cells in layer I of the neocortex, in cortical layers
2-6 and while matter and in the developing hippocampus and
dentate gyrus of day 0 prenatally-infected neonatal mice when
compared to sham-infected neonatal brains. Cell density values
showed decline in reelin expression in cortical and hippocampal
layers II-VI and white matter of infected neonates. Quantitation
of calretinin and nNOS immunoreactive CR cells in layer I of
infected and control brains showed no change in cell count
indicating that loss of reelin may be mostly due to decreased
synthesis or increased destruction of reelin secondary to
prenatal viral infection. Moreover, cortical, hippocampal and
hemispheric brain areas decreased significantly in infected
brains. This is the first report of a deleterious effect of
prenatal viral infection on developing brain causing a reduction
in the expression of reelin, one of several important molecules
thought to direct the correct lamination of the evolving brain.
Results of these experiments involving this potential animal
model may have a bearing on the mechanisms responsible for the
genesis of schizophrenia.
(Supported by NARSAD, MMF, Univ. Minn.
Faculty seed grant [SHF] and N01-AI-35 178 grant by NIH [RWS]).