Prenatal Human Influenza Viral Infection in Mice Decreases the Expression of Reelen in the Neonatal Cortex and Hippocampus

VIRAL INFECTION IN MICE DECREASES THE EXPRESSION OF REELIN IN THE

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

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 2^nd 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