Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.
These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.
Dysfunctional dopaminergic (DAergic) neurotransmission between the substantia nigra pars compacta (SNc) and the dorsal striatum (the nigrostriatal pathway) causes several prominent movement disorders (e.g. the motor symptoms of Parkinson's disease, dystonias and dyskinesias). Both too much and too little DA signalling can be problematic and nigrostriatal DAergic transmission is maintained at normal levels by several homeostatic mechanisms acting over timescales of milliseconds to weeks: e.g. binding of DA to tyrosine 3-monooxygenase (EC 1.14.16.2) (tyrosine Received November 1, 2010; revised manuscript received December 13, 2010; accepted December 14, 2010. Address correspondence and reprint requests to T. D. Aumann, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria, Australia 3010. E-mail: tim.aumann@florey.edu.auAbbreviations used: D2R, D 2 dopamine receptor; DA, dopamine; EGF, epidermal growth factor; FGF, fibroblast growth factor; GDNF, glial cellderived neurotrophic factor; GFP, green fluorescent protein; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; RRF, retrorubral field; SDS, sodium dodecyl sulfate; SK, small-conductance, Ca 2+ -activated potassium; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase; TTX, tetrodotoxin; VTA, ventral tegmental area. AbstractStriatal delivery of dopamine (DA) by midbrain substantia nigra pars compacta (SNc) neurons is vital for motor control and its depletion causes the motor symptoms of Parkinson's disease. While membrane potential changes or neuronal activity regulates tyrosine hydroxylase (TH, the rate limiting enzyme in catecholamine synthesis) expression in other catecholaminergic cells, it is not known whether the same occurs in adult SNc neurons. We administered drugs known to alter neuronal activity to mouse SNc DAergic neurons in various experimental preparations and measured changes in their TH expression. In cultured midbrain neurons, blockade of action potentials with 1 lM tetrodotoxin decreased TH expression beginning around 20 h later (as measured in real time by green fluorescent protein (GFP) expression driven off TH promoter activity). By contrast, partial blockade of small-conductance, Ca 2+ -activated potassium channels with 300 nM apamin increased TH mRNA and protein between 12 and 24 h later in slices of adult midbrain. Twoweek infusions of 300 nM apamin directly to the adult mouse midbrain in vivo also increased TH expression in SNc neurons, measured immunohistochemically. Paradoxically, the number of TH immunoreactive (TH+) SNc neurons decreased in these animals. Similar in vivo infusions of drugs affecting other ion-channels and receptors (L-type voltage-activated Ca 2+ channels, GABA A receptors, high K + , DA receptors) also increased or decreased cellular TH immunoreactivity but decreased or increased, respectively, the number of TH+ cells in SNc. We conclude that in adult SNc neurons: (i) TH expression is activity-dependent and begins to change 20 h following sustained chang...
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