Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

Abstract

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulindependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.

Immune Dysfunction in Tourette Syndrome

“…Stereotactic striatal infusion of patients' antibodies in rodents gave inconsistent results [47,48]. whereas active immunisation with rheumatogenic streptococcal strains led to the development of rodent models with an antibody-mediated behavioural disorder with some face validity also for tic disorders [49,50]. In one of these studies, a pathogenic role for anti-human D1/D2 dopamine receptor antibodies has been postulated, but their presence in a subgroup of patients with TS is still unknown and the object of ongoing research [50].…”

“…whereas active immunisation with rheumatogenic streptococcal strains led to the development of rodent models with an antibody-mediated behavioural disorder with some face validity also for tic disorders [49,50]. In one of these studies, a pathogenic role for anti-human D1/D2 dopamine receptor antibodies has been postulated, but their presence in a subgroup of patients with TS is still unknown and the object of ongoing research [50]. Immune-modifying treatments like plasma exchange and intravenous immunoglobulins are not beneficial in unselected populations of TS patients refractory to less invasive therapies [51], but might be effective in reducing obsessive-compulsive symptoms and tics in youngsters fulfilling criteria for PANDAS [52].…”

Paraneoplastic syndromes and autoimmune encephalitis

“…Similar approaches have been recently used to identify the Delta/Notch-like epidermal growth factor-related receptor (DNER) as the target of Tr antibodies in patients with cerebellar degeneration and Hodgkin lymphoma, 5 and the dopamine receptor (D1, D2) as autoantigen of nonparaneoplastic chorea and other neuropsychiatric disorders. 6 …”

Multidisciplinary Clinic Dedicated to Treating Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome: Presenting Characteristics of the First 47 Consecutive Patients

“…As GAS infections in youth are common and possibly coincidental in this population, it is also difficult to establish causality in those patients who test positive. However, there has been a substantial body of literature linking GAS infections with OCD, eating restriction, and movement disorders including chorea and tics (Husby et al 1976;Swedo et al 1989Swedo et al , 1993Swedo et al , 1998Mercadante et al 2000;Leonard and Swedo 2001;Kirvan et al 2003;Hoffman et al 2004;Singer et al 2004;Kirvan et al 2006Kirvan et al , 2007Murphy et al 2007;Yaddanapudi et al 2010;Brimberg et al 2012;Lotan et al 2014;Toufexis et al 2014;Williams and Swedo 2014). …”