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Some children develop obsessive compulsive disorder (OCD) symptoms quite suddenly, often after an infectious illness such as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS).  It has been hypothesized that these symptoms derive from antibodies that cross-react with cells in the brain, causing local brain inflammation and impairing brain circuit function. However, this has been somewhat controversial, in large part because these antibodies have proven difficult to identify.  A new study published in the American Journal of Psychiatry by a team of Yale scientists examined this phenomenon.

“We used a somewhat different approach from what has been done before,” senior author Chrisotpher Pittenger told us, “hoping to find new evidence for the existence of these antibodies and develop some insight into how they may perturb brain function.”

Pittenger is Co-Director of the Neuroscience Research Training Program at Yale University School of Medicine. Pittenger’s lab has spent years examining the contribution of different specific cell types, especially interneurons, to the function of the basal ganglia, a brain circuitry implicated in OCD, Tourette syndrome, and PANDAS. He told us they went into this study looking very broadly for antibody binding in the brain, but they were definitely primed to look for binding to interneurons.

“PANDAS can be devastating,” Pittenger told us. “It is somewhat controversial and it is not well understood. This combination of characteristics made it an exciting place to do some research and try to move the field forward.”

Previous attempts to identify pathogenic antibodies in PANDAS have focused on finding the specific molecules to which they bind. Some have looked at specific candidate molecules, others have taken a broader approach but have examined antibody binding under very artificial conditions, which may have limited their ability to yield replicable findings.

“We took a different approach,” Pittenger told us. “We looked for what cells the pathogenic antibodies bind to, rather than the molecules. This allows us to use different techniques, and lets us find consistent binding patterns across cases even if the specific molecules being bound differ. We also looked at binding in intact brain tissue (both mouse and human), rather than isolated molecules.” 

Researchers found that antibodies from children with PANDAS bound more than controls to specific interneurons in the striatum, the cholinergic interneurons (CINs). There was no elevated binding to any of the other cells looked at. In the CINs, antibody binding causes reduced cell activity, and binding is reduced when symptoms improve after treatment. 

“These CINs are very interesting cells,” Pittenger told us. “We already know from the work of my colleague Flora Vaccarino that they are reduced in number in adults with Tourette syndrome, a related condition, and we know from my own lab’s work that when we disrupt their function in mice we get repetitive behaviors that may capture aspects of tics. So finding antibodies that bind to these cells and reduce their function leads directly to a plausible theory about what’s happening in the brain of children with PANDAS.”

Researchers weren’t looking specifically for binding to the CINs. There are several other cell types to which binding would also make sense, Pittenger told us, but they didn’t see them. This seems to be a pretty specific phenomenon, at least according to their data thus far.

“We think this is an important step forward in understanding what’s going on in the brains of children with PANDAS,” Pittenger told us. “But I’d still call it a model, or a theory. I suspect that there will be variations in this theme in different kids. I don’t expect that the disorder proceeds identically in all cases. And our findings aren’t yet to the point of providing a diagnostic test or of guiding treatment. More work is needed to get to that point.”