Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity
Jian Xu1, Rong-Jian Liu1, Shaylyn Fahey1
1Department of Psychiatry (Xu, Liu, Fahey, Frick, Duman, Williams, Pittenger), Child Study Center (Leckman, Vaccarino, Pittenger), Department of Pediatrics (Leckman), and Department of Neuroscience (Vaccarino), Yale University School of Medicine, New Haven, Conn.; Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo (Frick); Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School (Williams), Boston; Pediatrics and Developmental Neuroscience Branch, NIMH, Bethesda, Md. (Swedo); PANDAS Physicians Network (Swedo); and Interdepartmental Neuroscience Program, Yale University, New Haven, Conn. (Pittenger).
Insights
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) involve IgG antibodies targeting striatal cholinergic interneurons (CINs), leading to rapid-onset OCD symptoms. Treatment reducing this antibody binding correlates with symptom improvement.
Area of Science:
- Neuroscience
- Immunology
- Pediatric Psychiatry
Background:
- Pediatric obsessive-compulsive disorder (OCD) can emerge rapidly, sometimes post-infection, a condition termed PANDAS.
- PANDAS is hypothesized to involve autoimmune responses targeting brain antigens, potentially affecting striatal cholinergic interneurons (CINs).
- Previous studies suggest IgG from PANDAS patients binds to CINs, implicating them in tic disorders and repetitive behaviors.
Purpose of the Study:
- To replicate and extend findings on PANDAS antibodies targeting CINs.
- To investigate the cellular effects of PANDAS antibodies on CINs.
- To correlate antibody binding with symptom severity and treatment response.
Main Methods:
- Ex vivo analysis of IgG binding to human and mouse brain slices incubated with serum from PANDAS patients and controls.
- Correlation of IgG binding with clinical symptom measures.
- Assessment of neural activity in mouse brain slices using molecular and electrophysiological markers after serum incubation.
Main Results:
- IgG from PANDAS patients consistently bound to CINs across three cohorts, unlike controls.
- Post-treatment (IVIG) serum showed reduced IgG binding to CINs, correlating with symptom improvement.
- Baseline PANDAS sera decreased striatal CIN activity and altered their electrophysiology in mouse slices.
Conclusions:
- Striatal CINs are a critical cellular target in PANDAS, contributing to rapid-onset OCD pathophysiology.
- These findings may extend to other related neurological or psychiatric conditions.
- Targeting CINs could be a therapeutic strategy for PANDAS and similar disorders.
Objective:
Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons.
Methods:
Binding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording.
Results:
IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs.
Conclusions:
These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.
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