Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring

Abstract

Epidemiological data suggest a relationship between maternal infection and a high incidence of schizophrenia in offspring. An animal model based on this hypothesis was made by injecting double-stranded RNA, polyinosinic-polycytidylic acid (poly-I:C), into early pregnant mice, and their offspring were examined for biochemical and histological abnormalities. Mouse brains were examined with special reference to oligodendrocytes, which have been implicated in several neurodevelopmental disorders. We detected a significant decrease of myelin basic protein (MBP) mRNA and protein at early postnatal periods in poly-I:C mice. MBP immunocytochemistry and electron microscopy revealed that the hippocampus of juvenile poly-I:C mice was less myelinated than in PBS mice, with no significant loss of oligodendrocytes. In addition, axonal diameters were significantly smaller in juvenile poly-I:C mice than in control mice. These abnormalities reverted to normal levels when the animals reached the adult stage. These findings suggest that retarded myelination and axonal abnormalities in early postnatal stages caused by maternal immune activation could be related to schizophrenia-related behaviors in adulthood.

Prenatal Exposure to the Viral Mimetic Poly I:C Alters Fetal Brain Cytokine Expression and Postnatal Behaviour

“…Whereas previous studies have described behavioural abnormalities in adult animals after poly I:C treatment in pregnancy [18,20,22], the emergence of symptoms in childhood and early adolescence is an important finding, since some mental illnesses such as autism, ADHD and schizophrenia, thought to be provoked by maternal viral illness during pregnancy, emerge at this stage of life. While the dose of poly I:C used in this study was higher than that used in our previous study [45], it is similar to that used in other studies with conventional mice or rats which produce altricial offspring.…”

“…Administration of poly I:C in rodents has been shown to cause an increase in inflammatory cytokines and plasma corticosterone, to induce a sickness behaviour syndrome including a febrile response, and to reduce appetite and decrease body weight [14,15,16]. Previous studies have described behavioural abnormalities in offspring born to pregnant mice and rats given poly I:C during gestation [17,18,19,20,21,22,23,24,25], even though brain development in these rodents is much less advanced at birth than it is in human pregnancy. As a model of viral illness appropriate to second-trimester pregnancy in women, we have used the spiny mouse (Acomys cahirinus) , an animal whose brain development is more advanced by the time of birth [26].…”

“…In particular, we examined the effects of prenatal poly I:C administration on prepulse inhibition, which, in conventional rodents, has been used as a signature of a behavioural disorder closely associated with schizophrenia in humans [21,22,23,25]. Furthermore, the current study aimed to extend our previous findings [45] by using a higher dose of poly I:C (5 mg/kg), which has been consistently shown to cause deficits in prepulse inhibition and other behavioural abnormalities in rats and mice [17,19,25,46,47,48].…”

White Matter Injury and Autistic-Like Behavior Predominantly Affecting Male Rat Offspring Exposed to Group B Streptococcal Maternal Inflammation

“…In contrast, LPS-induced brain damage extends well beyond external capsule white matter, involving the internal capsule and corpus callosum, and including apoptotic signs and white matter astroglial and microglial proliferations [7,38,39,40,41]. Poly I:C-induced lesions are another specific pattern of brain damage affecting hippocampal neurons and also involving underlying myelin and oligodendrocytes [42]. Certain autistic-like traits have been reported following TLR3 and TLR4 activation, as well as in our GBS/TLR2 model of maternal immune activation.…”

A Critical Review of Models of Perinatal Infection

“…Finally, viral infection simulated by injection with polyinosinic-polycytidylic acid [poly(I:C), a synthetic double stranded viral RNA] of between 5-60 mg/kg in pregnant mice has been associated with impairment of cerebellar and hippocampal development and long-term behavioral deficits [38,39,40,41]. Similarly, in the spiny mouse ( Acomys cahirinus ), in which brain maturation at birth is relatively similar to term human infants, 5 mg/kg poly(I:C) at 20 days of gestation (term is 39 days) led to downregulation of tumor necrosis factor-α in the fetal brain, with behavioral abnormalities in sensorimotor function, social interaction, memory, and learning in the pups [42].…”