In conjunction with our previous results (47), the effect has now been seen using two different experimental approaches (and binding to denatured protein (17, 18) or to heterologous cells overexpressing dopamine receptors (64). types, more than IgG from controls, in three independent cohorts of patients. IVIG reduced IgG binding to CINs; 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. INTRODUCTION Obsessive-compulsive disorder (OCD) occurs in 1% to 3% (+)-Apogossypol of children and adolescents in the United States, and a comparable proportion worldwide (1, 2). In a subset of pediatric OCD cases, onset of neuropsychiatric symptoms is strikingly abrupt; this has been termed pediatric acute-onset neuropsychiatric syndrome, or PANS (3, 4). In some, symptom onset is temporally associated with an infectious illness, often with group A beta-hemolytic streptococcus (GAS) (5). This natural history, and the presence of a constellation of characteristic associated symptoms (e.g. separation anxiety, severely restricted food intake, enuresis, choreiform movements, handwriting deterioration), suggests that this presentation may represent a discrete clinical entity, which has been termed to alter activation of calcium calmodulin protein kinase II (CaMKII) in a human neuroblastoma cell line and to reduce cyclic adenosine monophosphate (cAMP) in a mouse fibroblast cell line expressing human D2R (15, 18). Immune modulatory treatments such as plasmapheresis and intravenous immunoglobulin (IVIG) have shown promise in some trials, though others have been inconclusive (19C22). Antibiotic prophylaxis has also been found to be effective in reducing the rate of recurrent episodes in some studies (23), CD86 though again, others have not found clear benefit (24, 25). In animal studies, immunization with GAS can produce abnormal behavior, and passive transfer of sera from these GAS-exposed rodents to naive animals can recapitulate some of these abnormalities (26, 27). Thus, convergent evidence from multiple studies supports the concept of immunologic pathogenesis in PANDAS, but non-replication has been common, and the literature has yet to converge on a clear understanding of the pathophysiology of the condition C or even if it is appropriately conceived as a discrete entity. The pathophysiology of OCD and tic disorders is incompletely understood (28, 29). Substantial evidence implicates dysregulation of cortico-basal ganglia circuits in both conditions (30C35), as well as in PANDAS. The striatum, which consists in primates of the caudate and putamen, is the primary input nucleus of the basal ganglia and integrates synaptic inputs from limbic and cortical regions (36). The vast majority of neurons in the striatum (~95% in rodents) consists of GABAergic medium spiny neurons (MSNs). Only a small fraction (~5%) are interneurons (37), of which GABAergic interneurons are the most abundant. They can be classified based on their expression of markers such as parvalbumin (PV), somatostatin (SOM), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). A distinct, small population of large, tonically active cholinergic interneurons (CINs) is characterized by expression of choline acetyltransferase (ChAT). Although few in number, these interneurons are key regulators of striatal function (+)-Apogossypol (38C41). Both CINs and PV-expressing GABAergic interneurons (+)-Apogossypol are reduced in number in the caudate and putamen of Tourette syndrome (+)-Apogossypol (TS) individuals (42C44). Transcriptomic analysis of post-mortem striatum from TS similarly reveals reduced expression of interneuron-associated genes (43). Experimental depletion of these cells in developmentally normal mice produces repetitive behavioral pathology (45, 46), suggesting that this deficit is causally related to symptomatology. In a small pilot study (N=5), we found that IgG antibodies from children with rigorously characterized PANDAS showed significantly higher binding to CINs in mouse than IgG from age- and gender-matched healthy controls. This elevated IgG binding to CINs resolved in parallel with symptom improvement in serum collected after IVIG treatment (47). This suggests that binding of IgG to striatal CINs may contribute to pathophysiology in PANDAS. Here, (+)-Apogossypol we confirm elevated IgG binding to CINs, but not to other striatal neurons, both.
In conjunction with our previous results (47), the effect has now been seen using two different experimental approaches (and binding to denatured protein (17, 18) or to heterologous cells overexpressing dopamine receptors (64)
