A group of researchers has recently shown that plasma serum taken from kids who have been diagnosed with PANDAS and who also responded well to IVIG treatment contained antibodies that bind to and inhibit a specific type of neuron found in the basal ganglia.
It has been proposed that PANDAS results from post-infectious antibodies that target the basal ganglia. The striatum consists of the caudate and putamen. It is the largest part of the basal ganglia and is its primary input nucleus and serves to integrate synaptic inputs from limbic and cortical regions. Only about 5% of the neurons in the striatum are so-called interneurons. Interneurons connect different regions of the brain and form communication nodes that are important for coordinating activities. Interneurons can be classified based on their expression of various markers. A small subset of interneurons, called cholinergic interneurons (CINs), is characterized by expression of choline acetyltransferase (ChAT). Although few in number, these CINs are key regulators of basal ganglia function. CINs regulate motor function and are known to be reduced in number in adults who have Tourette’s syndrome. Also, selective experimental depletion of CINs in healthy mice yields repetitive behavioral disorders. These facts suggest CIN dysregulation could play a role in PANDAS.
In a pilot study, antibodies from 5 children with rigorously characterized PANDAS showed significantly higher binding to CINs in mouse striatal tissue than antibodies from age- and gender-matched healthy controls. The experiments generally involve incubating striatal neurons with the subject’s plasma serum, which contains IgG antibodies, and then using fluorescent staining and imaging techniques to detect and quantify the antibodies bound to the neuron. The results of the pilot study were confirmed by elevated antibody binding to CINs, but not to other striatal neurons, both in the original 5 PANDAS patients and in two additional independent groups of PANDAS patients, and in both mouse and post-mortem human striatal tissue. The results were consistent across 27 PANDAS patients in total. Moreover, the researchers showed that the antibody binding from the PANDAS patients inhibited activity of the CINs. Finally, antibodies taken from the PANDAS patients after successful treatment with IVIG exhibited reduced binding to the CINs compared to the antibodies taken before IVIG treatment. Also, the reduction in antibody binding was strongly correlated with the amount of symptom improvement.
The findings of these researchers support a novel hypothesis that PANDAS involves antibodies binding to and inhibiting activity of CINs in the basal ganglia. They also suggest important directions for future research, validation of PANDAS diagnoses, and future treatments.
Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity, Jian Xu, Ph.D., Rong-Jian Liu, Ph.D., Shaylyn Fahey, B.S., Luciana Frick, Ph.D., James Leckman, M.D., Ph.D., Flora Vaccarino, M.D., Ronald S. Duman, Ph.D., Kyle Williams, M.D., Ph.D., Susan Swedo, M.D., Christopher Pittenger, M.D., Ph.D.
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