Maternal brain reactive antibodies profile in autism spectrum disorder: an update.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with multifactorial etiologies involving both genetic and environmental factors. In the past two decades it has become clear that in utero exposure to toxins, inflammation, microbiome, and antibodies (Abs), may play a role in the etiology of ASD. Maternal brain-reactive Abs, present in 10-20% of mothers of a child with ASD, pose a potential risk to the developing brain because they can gain access to the brain during gestation, altering brain development during a critical period. Different maternal anti-brain Abs have been associated with ASD and have been suggested to bind extracellular or intracellular neuronal antigens. Clinical data from various cohorts support the increase in prevalence of such maternal brain-reactive Abs in mothers of a child with ASD compared to mothers of a typically developing child. Animal models of both non-human primates and rodents have provided compelling evidence supporting a pathogenic role of these Abs. In this review we summarize the data from clinical and animal models addressing the role of pathogenic maternal Abs in ASD. We propose that maternal brain-reactive Abs are an overlooked and promising field of research, representing a modifiable risk factor that may account for up to 20% of cases of ASD. More studies are needed to better characterize the Abs that contribute to the risk of having a child with ASD, to understand whether we can we predict such cases of ASD, and to better pinpoint the antigenic specificity of these Abs and their mechanisms of pathogenicity.

In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to behavioral abnormalities resembling autism spectrum disorder in male mice.

The concept that exposure in utero to maternal anti-brain antibodies contributes to the development of autism spectrum disorders (ASD) has been entertained for over a decade. We determined that antibodies targeting Caspr2 are present at high frequency in mothers with brain-reactive serology and a child with ASD, and further demonstrated that exposure in utero to a monoclonal anti-Caspr2 antibody, derived from a mother of an ASD child, led to an-ASD like phenotype in male offspring. Now we propose a new model to study the effects of in utero exposure to anti-Caspr2 antibody. Dams immunized with the extracellular portion of Caspr2 express anti-Caspr2 antibodies throughout gestation to better mimic the human condition. Male but not female mice born to dams harboring polyclonal anti-Caspr2 antibodies showed abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as repetitive behaviors and impairments in novelty interest in the social preference test as adults. These data supporting the pathogenicity of anti-Caspr2 antibodies are consistent with the concept that anti-brain antibodies present in women during gestation can alter fetal brain development, and confirm that males are peculiarly susceptible.

Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus.

Increasing evidence indicates that chemotherapy results in long-term effects on cognitive dysfunction in some cancer survivors. While many studies have established the domains of cognition and corresponding regions in the brain most affected, little is revealed about the potential molecular mechanisms that mediate these adverse changes after treatment. The effects of chemotherapy on the brain are likely attributed to various mechanisms, including oxidative stress and immune dysregulation, features that are also reminiscent of cognitive aging. We have investigated the cognitive effects of a cocktail composed of doxorubicin and cyclophosphamide (AC-chemo) in a surgical ovariectomized rodent model. In this study, we address whether the levels of pro-inflammatory cytokines and oxidative stress-responsive gene markers are altered in the CNS of rats treated with systemic AC-chemo. We further evaluated the levels of nucleic acids modified by oxidative stress in the hippocampus using both immunohistochemical and Northern blotting techniques with a monoclonal antibody against 8-hydroxyguanosine (8-OHG) and 8-OHdG base lesions. We demonstrate that ERK 1/2 and JNK/SAPK signaling activities are elevated in the hippocampus of AC-chemo rats. The levels of pro-inflammatory, oxidative stress-responsive, and RNA/DNA damage markers were also higher in drug-injected animals relative to saline controls. The results indicate that the effects of AC chemotherapy are associated with oxidative damage and a global stress response in the hippocampus. These alterations in the molecular signature of the brain may underlie the processes that contribute to cognitive impairment after treatment.