Maternal autoimmune antibodies alter the dendritic arbor and spine numbers in the infragranular layers of the cortex

Abstract

An association between maternal IgG antibodies reactive against proteins in fetal brain and an outcome of autism in the child has been identified. Using a mouse model of prenatal intraventricular administration of autism-specific maternal IgG, we demonstrated that these antibodies produce behavioral alterations similar to those in children with ASD. We previously demonstrated that these antibodies bind to radial glial stem cells (RG) and observed an increase in the number of divisions of translocating RG in the developing cortex. We also showed an alteration in brain size and as well as a generalized increased of neuronal volume in adult mice. Here, we used our intraventricular mouse model of antibody administration, followed by Golgi and Neurolucida analysis to demonstrate that during midstages of neurogenesis these maternal autism-specific antibodies produced a consistent decrease in the number of spines in the infragranular layers in the adult cortical areas analyzed. Specifically, in the frontal cortex basal dendrites of layer V neurons were decreased in length and volume, and both the total number of spines—mature and immature—and the spine density were lower than in the control neurons from the same region. Further, in the occipital cortex layer VI neurons presented with a decrease in the total number of spines and in the spine density in the apical dendrite, as well as decrease in the number of mature spines in the apical and basal dendrites. Interestingly, the time of exposure to these antibodies (E14.5) coincides with the generation of pyramidal neurons in layer V in the frontal cortex and in layer VI in the occipital cortex, following the normal rostro-caudal pattern of cortical cell generation. We recently demonstrated that one of the primary antigens recognized by these antibodies corresponds to stress-induced phosphoprotein 1 (STIP1). Here we hypothesize that the reduction in the access of newborn cells to STIP1 in the developing cortex may be responsible for the reduced dendritic arborization and number of spines we noted in the adult cortex.

Autism-specific maternal autoantibodies produce behavioral abnormalities in an endogenous antigen-driven mouse model of autism

“…In a 2014 study, mice receiving a single intraventricular injection on embryonic day 14 of human IgG from maternal plasma with the 37 and 73 kDa autoantibodies resulted in atypical behaviors, including stereotypical self-grooming and increased repetitive behaviors, relative to mice similarly injected with maternal IgG from mothers of neurotypical controls 23 . Two subsequent investigations using the same technique showed neuroanatomical changes in the offspring, including increased radial glial cell proliferation along with accelerated migration, reduced numbers of cortical dendritic spines, as well as increased brain and neuron size 21, 22 . A related study utilizing a passive transfer approach in rhesus macaques demonstrated higher levels of motor activity and stereotypies among in offspring of macaque dams prenatally exposed to autoantibody-positive ASD IgG, supporting potentially pathogenic IgG present in maternal circulation 25 .…”

Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders

“…In rodents, maternal autoantibodies administered during gestation were found to be able to migrate into the cortical parenchyma and alter coronal development by binding to radial glial cells in the ventricular zone and increased the number of neuronal precursor cells in the subventricular zone, increasing brain size and weight. Administration of autoantibodies also led to decreased numbers of mature dendritic spines in the adult cortex of mice, with STIP1 blockade being the likely culprit due to its importance in neuritogenesis, the sprouting of neurites that later develop into dendrites (Martinez-Cerdeno et al, 2016 ; Ariza et al, 2017 ). Mice exposed to maternal autoantibodies during the embryonic stage displayed ASD-like behaviors including increased repetitive behaviors and altered social interactions (Camacho et al, 2014 ).…”

Maternal-Autoantibody-Related (MAR) Autism: Identifying Neuronal Antigens and Approaching Prospects for Intervention

“…Purified patient IgG containing 37/73 kDa antibodies was injected into the cerebral ventricles of mice in utero, and the brains were examined 2 h or 2 days later. In two papers [ 44 , 45 ] the authors showed that the IgG recognised radial glial cells, increased ventricular zone cell proliferation and subsequent cortical neurons and reduced dendritic spines. As in the previous studies from Braunschweig et al [ 25 ] and Bauman et al [ 31 ], this indicated potential pathogenicity of the IgG but did not prove that the 37/73 antibodies were responsible.…”

“… Monoclonal CASPR2 derived from 1 mother of an autistic child Control = Non-brain-reactive human antibody, B1 Martínez-Cerdeño et al (2016) [ 44 ] Purified IgG from mothers of autistic children with paired 37/73 kDa band reactivity was injected into pregnant mice: IgG recognised radial glial cells, increased subventricular zone and extra-cortical cell proliferation and increased both the size and weight of adult brains and the size of adult cortical neurons. MAU = 4 (selected for paired 37/73 kDa reactivity) MTD = 5 (selected to lack 37 and 73 kDa reactivity) Plasma samples were from the CHARGE study at the University of California and were taken 1–5 years after pregnancy Ariza et al (2017) [ 45 ] Purified IgG from mothers of autistic children with paired 37/73 kDa band reactivity was injected into pregnant mice: IgG reduced dendritic spine number and density in the frontal and occipital cortices. MAU = 1 (selected for paired high-titre 37/73 kDa reactivity) MTD = 1 (selected to lack 37 and 73 kDa reactivity) Plasma samples were from the CHARGE study at the University of California and were taken 1–5 years after pregnancy Coutinho et al (October 2017) [ 51 ] IgG from two patients with CASPR2-antibody encephalitis injected into pregnant mice: Adult offspring showed social interaction deficits, abnormally located glutamatergic neurons in layers V-VI of the somatosensory cortex, microglial overactivation and a reduction in glutamatergic synaptic profile density in the prefrontal and somatosensory cortices.…”