32104
Activation of Microglia Mediates ASD like Phenotype in Mice Following in Utero Exposure to Anti-Caspr2 Antibodies
Autism Spectrum Disorder (ASD) is a devastating condition with an incidence that continues to rise worldwide. The rising incidence points to environmental factors. We have been particularly interested in the contribution of maternal antibody to ASD, as we observed that over 10% of mothers of an ASD child harbor anti-brain antibodies. We demonstrated that one such pathogenic maternal antibody is anti-Caspr2 antibody, a monoclonal antibody generated from a mother with anti-brain antibodies and an ASD child. A single in utero exposure to this antibody led to brain and behavior abnormalities in male but not in female mice. Since we determined that approximately 40% of mothers with an ASD-child and with anti-brain reactivity expressed anti-Caspr2 reactivity, anti-Caspr2 reactivity might be dominant brain specificity and have an important translational impact.
Objectives:
To understand how in utero exposure to anti-Caspr2 antibodies causes persistent neurologic abnormalities.
Methods:
We have developed a new model with endogenous antibody production in which dams harbor anti-Caspr2 antibodies throughout gestation, to better mimic the human condition, and to ascertain the pathogenicity of a spectrum of anti-Caspr2 antibodies. Six week old C57Bl/6 female mice were immunized with the extracellular region of human Caspr2. Control female mice are immunized with adjuvant only. IgG titers against Caspr2 are determined by a cell based assay against both human and mouse Caspr2. When antibody titers to mouse Caspr2 are 1:3000 immunized mice are mated with naïve males to generate timed pregnancies. We assessed neuropathology and behavior of mice exposed in utero to polyclonal anti-Caspr2 antibodies.
Results:
Male, but not female, fetuses of dams harboring anti-Caspr2 antibodies showed thinning of the cortical plate, reduced proliferating cells at E15.5, and abnormal neuronal migration similar to our previous results in male fetuses exposed in utero to maternal monoclonal anti-Caspr2 antibody. Adult male but not female mice born to dams harboring anti-Caspr2 antibodies showed an an impaired interest in social novelty in the social preference test, and repetitive/ stereotypic behavior; they buried significantly more marbles than control mice in the marble burying test, and spent more time grooming. We found that the brain of mice exposed in utero to anti-Caspr2 antibodies exhibited decreased dendritic complexity of excitatory neurons. A potential mechanism for decreased dendritic complexity is engulfment of dendritic processes by activated microglia. Indeed, we observed activated microglia identified by localization of CD68 with Iba1, cell shape and number of extended processes. We are currently testing if depletion of microglia in the offspring will prevent the decreased dendritic arborization.
Conclusions:
We show in a new mouse model that exposure in-utero to anti-Caspr2 reactive antibodies induces neurodevelopmental effects in the offspring that can be observed already during the embryonic stage. These antibodies lead to an ongoing activation of microglia in the adult mice. Microglia are druggable targets; therefore modulating microglia might be a potential new therapy.