Of Mice and PANDAS

There is evidence from studies of PANDAS (pediatric autoimmune neuropsychiatric disorders) and possibly also Tourette syndrome, obsessive compulsive disorder and Syndenham’s chorea, that streptococcus infection can lead to repetitive/stereotyped behaviors and tics. The fact that treatment with strong antibiotics or manipulation of serum antibodies can ameliorate or even cure many PANDAS patients strongly supports this notion. Moreover, elevated levels of anti-strep antibodies are correlated with clinical severity, and it is postulated that these antibodies cross-react with, and bind to, neurons in the parts of the brain that control these behaviors. To find out if this is really the mechanism for how strep infection alters behavior, and to investigate how to prevent it, animal models are essential. Previous work showed that injection of serum from Tourette patients into the brains of rats was able to induce stereotyped behaviors such as head shaking or repetitive oral movements (although some later studies failed to reproduce these findings). Moreover, intravenous or subcutaneous injection of mice with strep proteins or antibody from strep infected mice induced abnormal behaviors in the recipient mice. However, these earlier studies circumvented the blood brain barrier (BBB), which normally protects the brain, by direct injection into the brain or by temporarily opening the BBB to allow entry of the antibodies. Thus it is interesting that a new paper by Danhui Zhang and colleagues reports that a single subcutaneous injection of anti-strep antibodies into mice quickly induces stereotyped behaviors such as head bobbing and intense self-grooming. Injection of control antibodies does not have these effects. Importantly, the anti-strep antibodies also stimulate activation of certain genes in brain areas relevant for these behaviors, and these antibodies are also found in the same brain areas. These results strongly support the hypothesis that strep infection causes the production of antibodies that can cross react with the brain and directly alter behavior. It is nonetheless surprising that, in this new report, no effort was made to disrupt the BBB and yet the antibodies were found to enter the brain [the methods section of this paper was not entirely clear on this point, but contacting the author cleared this up]. By way of explanation, the authors suggest that the strain of mice they used is particularly susceptible to stress, and the mice were stressed by the injection and by the subsequent behavioral testing. Prior animal work showed that stress can temporarily open the BBB. This raises the possibility that stress could also be relevant in infection induction of the human conditions noted above.

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