Auto-antibodies form mind growth in myriad methods | Spectrum
Immune response: rats exposed to certain antibodies in the womb have the molecules (green) in their brain.
Courtesy Matthew Bruce / UC Davis
Prenatal exposure to maternal antibodies can contribute to autism in different ways, depending on the antibodies involved, new unpublished studies suggest.
Two research teams presented the results virtually at the Society for Neuroscience’s annual meeting in 2021. (Links to abstracts may only work for registered conference participants.)
A pregnant woman’s antibodies can pass through the placenta to her developing fetus. Although most antibodies are useful and protect the fetus from pathogens, certain forms – so-called “autoantibodies” – can also attack its brain cells and change its development.
Previous studies show that women with autistic children are more likely to have these autoantibodies than women with non-autistic children. And mice, rats, and monkeys exposed to these autism-linked autoantibodies in the womb show some characteristics that are reminiscent of autism.
The two new working lines indicate the underlying mechanisms.
In one study, researchers challenged female mice to produce autoantibodies by repeatedly injecting them with part of a protein called CASPR2, which is encoded by the autism-linked gene CNTNAP2. The male offspring of these animals, but not their female offspring, exhibited autism-like behaviors such as repetitive behaviors and decreased sociability, the researchers found.
The male offspring also had atypical neurons in their hippocampus, a region of the brain involved in learning and memory. Compared to those of the female offspring and controls, the cells of the exposed males had fewer dendrites, the arms of a neuron that receive signals from other cells, and fewer dendritic spines, the nodes at which synapses between the cells form.
Some dendritic circumcision, mediated by brain cells called microglia, is necessary for typical brain development. The exposed male mice, however, seem to have gone into full swing, the team found: The animals had an unusually high density of microglia in their hippocampus. And their microglia were thick, with shorter appendages – a hallmark of activated cells – and not thin with many spindly arms as in the control animals and the exposed females.
Microglia are activated during brain development and after brain injury, but it’s unclear what triggers activation in the cells of the model animals, says lead researcher Lior Brimberg, assistant professor of neuroimmunology at the Feinstein Institute for Medical Research in Manhasset, New York.
Treatment of the exposed male mice with the drug captopril, which is believed to suppress microglial activation, eliminated the differences in their microglia and normalized the appearance of their hippocampal neurons.
“There was a noticeable effect between the [levels of microglial] Activation and also dendritic branching “in mice given the anti-saline drug,” says Ben Spielman, a PhD student in Brimberg’s laboratory and the Donald and Barbara Zucker School of Medicine at Hofstra / Northwell in Hempstead, New York, who presented the work.
Compensation of differences:
In the other new study, another team injected female rats with a cocktail of peptides that target the autoantibodies found in some women with autistic children. The researchers then bred these rats after generating their own autoantibodies against the peptides.
Like the mice in Brimberg’s study, the offspring of these rats exhibited characteristics similar to autism, including decreased communication and sociability, and increased repetitive behavior. The rats also exhibited atypical brain development: exposed males exhibited changes in their sensory cortex and exposed animals of both sexes exhibited an atypical structure in the cerebellum and midbrain.
The model animals also differed from control animals in some of the metabolites present in their brains, the researchers found using magnetic resonance spectroscopy. Compared to controls, rats exposed to the autoantibodies in utero had higher taurine and lower choline levels, which can contribute to atypical development by disrupting the balance between neuronal excitation and inhibition or causing changes in myelination, says Matthew Bruce , a PhD student in Judy Van de Water’s laboratory at the University of California, Davis, who presented the work.
Bruce and his colleagues want to next investigate how these antibodies bind to neurons in culture and whether they are taken up by the cells. “That is the biggest direction of the future – understanding what is happening here at the cellular level,” says Bruce.
As for the differences in the two auto-antibody models of autism, like the sex differences seen in animals exposed to CASPR2 autoantibodies but not those given the autoantibody cocktail, Bruce says the field is them can reconcile.
Brimberg agrees. The different models could be associated with different autism subtypes, she suggests. “I hope that at some point in the future we will have enough data, enough knowledge” to be able to link them together, she says.
Read more reports from the Society for Neuroscience’s 2021 Annual Virtual Meeting.