Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders

Abstract

Human endogenous retroviruses (HERVs) are genetic elements resulting from relics of ancestral infection of germline cells, now recognized as cofactors in the etiology of several complex diseases. Here we present a review of findings supporting the role of the abnormal HERVs activity in neurodevelopmental disorders. The derailment of brain development underlies numerous neuropsychiatric conditions, likely starting during prenatal life and carrying on during subsequent maturation of the brain. Autism spectrum disorders, attention deficit hyperactivity disorders, and schizophrenia are neurodevelopmental disorders that arise clinically during early childhood or adolescence, currently attributed to the interplay among genetic vulnerability, environmental risk factors, and maternal immune activation. The role of HERVs in human embryogenesis, their intrinsic responsiveness to external stimuli, and the interaction with the immune system support the involvement of HERVs in the derailed neurodevelopmental process. Although definitive proofs that HERVs are involved in neurobehavioral alterations are still lacking, both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a neurodevelopmental disorders-associated biological trait in affected individuals and their parents.

Keywords: ASD animal model.; autism; endogenous retroviruses (ERVs); maternal immune activation; neurodevelopmental disorders.

Figure 1

The potential involvement of human endogenous retroviruses (HERVs) in the interaction among genetic vulnerability, environmental risk factors, and immune activation in complex neurodevelopmental disorders.

Figure 2

The abnormal endogenous retroviruses (ERVs) and cytokines expression from intrauterine life to adulthood in the first generation (F₁) prenatally exposed to valproic acid (VPA) could be due to the drug-induced epigenetic changes. ERVs activity (red lines) and cytokines expression (light blue lines) were represented both for VPA- and vehicle-treated mice.

Figure 3

Transgenerational inheritance of altered ERVs activity in the VPA-induced mouse models of autism spectrum disorders (ASD), potentially involved mechanisms. VPA exposure of the pregnant dam (F₀) leads a direct insult to the fetus (F₁) and to germ cells that will generate the F₂ generation, while the F₃ is the first generation not directly exposed. Transgenerational transmission of abnormal ERVs expression induced by VPA could be due to changes in the epigenetic status or of the ERVs copy number variation in the genome.