The effects of immune activation in the pathogenesis of neurodevelopmental disorders : in vivo and in vitro animal studies

Abstract

Schizophrenia and autism are psychiatric disorders with a presumed neurodevelopmental origin, characterised by clinical features and aetiologies that overlap at multiple levels. In addition to genetic susceptibility, epidemiological studies revealed an association between environmental factors and these disorders. Immune activation in response to infection at early gestation has been identified as one of the key risk factors. Little is known about the underlying mechanism during maternal immune activation (MIA), but extrinsic apoptotic dysregulation has been postulated to play a role in MIA infection. In particular, emerging studies suggest apoptosis without triggering whole cell demise, namely synaptic apoptosis, is a potential event that leads to the abnormal behaviours in the affected offspring.

In this study, C57BL/6N mice model was employed to investigate the impacts of viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure at gestation day 9 in the resultant male offspring in adulthood in vivo by different parameters, including magnetic resonance imaging (MRI), behavioural tasks that assess sensorimotor gating, exploratory and anxiety behaviours, and protein quantification in the apoptotic pathway. In parallel, the direct effect of Poly (I:C) treatment for 24 hours on extrinsic apoptotic proteins were determined in primary cortical neurons in vitro. It was hypothesised that MIA would result in brain volumetric changes subsequent to behavioural anomalies in the adult offspring with maternal exposure to Poly (I:C), for which abnormalities are normally pronounced by that time. In addition, the hypothesis that foetuses exposed to Poly (I:C) in early gestation stage would have increased expression level of apoptotic proteins of extrinsic types, namely Fas receptor, caspase-8 and the death effector caspase-3.

This study found that, although male adult offspring with early maternal exposure to Poly (I:C) had an increase in raw whole brain volume, this was not significant when body weight was included as a covariable. However, prenatal exposure caused behavioural features similar to those reported in schizophrenia and autism such as prepulse inhibition deficits, increased anxiety-level and higher locomotor activity in response to amphetamine challenge. On the other hand, a marked augmentation in caspase-8 level without any significant changes in Fas or caspase-3 was observed in the adult hippocampus. No alterations in the expression of selected apoptotic proteins were found in the embryonic cortical cells.

Overall the present studies suggested that acute exposure to infection during early fetal development causes a range of aberrations in brain anatomy, behaviour and biochemistry that are of relevance to the pathophysiology of schizophrenia and autism. The results suggest a potential involvement of synaptic apoptosis in cellular events underlying neurodevelopmental disorders.