Is paternal immune activation just as important as maternal immune activation? Time to rethink the bi-parental immune priming of neurodevelopmental model of schizophrenia

Abstract

The neurodevelopmental origin of schizophrenia is a paradigmatic etiological construct. Parental exposure to environmental adversities and altered parental immune and stress-regulatory pathways affect the neurodevelopment of the fetus and may enhance the risk of schizophrenia in offspring. With respect to the parental contribution to these neurodevelopmental aberrations, most research has been on the maternal contribution. Maternal Immune activation, induced by maternal infections has been identified as a key pathway in the neurodevelopmental model of schizophrenia. Recent understanding points towards the fact that both the maternal and paternal priming offers survival advantages of the offspring to pathogen exposure. However, notwithstanding common epigenetic mechanisms applicable to both sexes, there is a lack of empirical data on the effect of paternal immune activation on neurodevelopmental aberrations and the consequent risk of schizophrenia in offspring.Large birth-cohort studies suggest a comparable impact of maternal and paternal infections on the risk of schizophrenia in offspring. The link between maternal infection and the risk of schizophrenia is mediated by the elements of the immune system through induction of maternal immune activation and subsequent neural and immune developmental aberrations. The contribution of paternal immune activation to schizophrenia risk has not yet been adequately explored. It is rational to assume that paternal infections might also enhance the risk of schizophrenia in offspring through paternal immune activation leading to neuroimmunodevelopmental aberrations. However, the underlying mechanisms whereby paternal infections as well as paternal immune activation might confer the risk of schizophrenia in the offspring seem to be distinct from maternal infection as the modes of transfer of the maternal and paternal factors are different. Maternal immune priming during gestation seems primarily through the direct effect of soluble immune factors, while the paternal immune priming might be mediated predominantly by epigenetic processes or through the effect of modifying factors in sperm. An account of plausible underlying mechanisms linking paternal immune activation and risk of schizophrenia are highlighted in this article. Furthermore, we propose the possibility of bi-parental immune priming in driving the neuroimmunodevelopmental abnormality as a risk mechanism of schizophrenia. It is envisaged that the neuroimmunodevelopmental aberration-associated risk of schizophrenia could be the result of cumulative effects of maternal as well as paternal immune stimulation. Delineation of the underlying maternal and paternal immune priming mechanism(s) will have important implications in resolving dilemmas of schizophrenia etiology as well as prevention.