Tim D. Aumann

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders

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 Sydenhams chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourettes 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.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N‐methyl‐D‐aspartate receptor (NMDAR).

Remyelination Is Altered by Bone Morphogenic Protein Signaling in Demyelinated Lesions

Remyelination of the CNS involves the regeneration of mature oligodendrocytes by endogenous oligodendrocyte progenitor cells (OPCs). Previous studies have shown that bone morphogenic proteins (BMPs) inhibit the production of oligodendrocytes in the healthy CNS. However, there is currently no information on the influence of BMP signaling in vivo within demyelinated lesions of the brain or on subsequent remyelination. Here, we determine a role for BMP signaling in modulating oligodendrogliogenesis and remyelination in the brain following cuprizone-induced demyelination. We identified that BMP signaling is active in oligodendroglia and astrocytes within the demyelinated corpus callosum. Intraventricular infusion of BMP4 into the brains of mice during demyelination increased the proliferation of OPCs and, to a lesser extent, microglia and astrocytes in the corpus callosum. In contrast, infusion of Noggin, an extracellular antagonist of BMP4, increased the density of mature oligodendrocytes in the remyelinating corpus callosum. Additional evidence from myelin staining and electron microscopy indicates there is an increase in remyelinated axons in the corpus callosum of Noggin-infused mice. Thus, inhibition of endogenous BMP signaling during demyelination promotes mature oligodendrocyte regeneration and remyelination.

Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone‐induced demyelination

J. Neurochem. (2010) 115, 11–22.

Ramification and termination of single axons in the cerebellothalamic pathway of the rat.

There is increasing speculation that individual neurones in the cerebellar nuclei are involved in the control of complex multi‐joint movements rather than simple movements about a single‐joint. These neurones project predominantly to the primary motor cortex after relaying in the motor thalamus. Given a) that localised regions of the motor cortex control individual muscles which generally act about single joints and b) the relatively tight topographical arrangement of thalamocortical connections, it is reasonable to hypothesise that if cerebellar output neurones control single‐joint movements they are likely to project to localised areas of the motor thalamus, whereas if they project to more widespread regions they are likely to influence movements involving multiple joints. In this context, we have examined the ramifications and terminations of single anterogradely labelled axons in the cerebellothalamic pathway of the rat.

Neuronal activity regulates expression of tyrosine hydroxylase in adult mouse substantia nigra pars compacta neurons

J. Neurochem. (2011) 116, 646–658.

Projections from the cerebellar interposed and dorsal column nuclei to the thalamus in the rat: A double anterograde labelling study

It is generally agreed that cerebellar and lemniscal pathways project to largely separate areas of the thalamus and influence different functional areas of the cerebral cortex. Cerebellar afferents arise from neurones in the deep cerebellar nuclei and terminate in the ventral lateral group of thalamic nuclei or the “motor thalamus,” whereas lemniscal afferents arise from the dorsal column nuclei and terminate in the adjacent ventral posterior group of thalamic nuclei or “sensory thalamus.” However, it remains unclear whether or not these pathways converge onto thalamic neurones in the border zone between motor and sensory thalamus. The aim of this study was to compare directly the locations of cerebellar interposed and dorsal column nuclei terminals in the rat thalamus by using a double anterograde labelling technique. Microinjections of dextran‐tetramethylrhodamine and dextran‐fluorescein were made into the interposed and dorsal column nuclei, and labelled terminals in the thalamus were examined in the same sections. The labelled cerebellar and lemniscal terminals were located in separate areas throughout most of the ventral lateral and ventral posterior lateral nuclei, and there was only a limited region around the rostral border between these nuclei where the two groups of terminals came in close proximity to each other. In this common projection zone, however, cerebellar and lemniscal terminals seldom intermingled, and they mostly occupied separate, discreet areas. The results show that cerebellar and lemniscal fibres do indeed project to the border zone between the sensory and cerebellar thalamic nuclei, but they show practically no overlap in this region and are likely to influence separate thalamic neurones.

Oscillatory activity in forelimb muscles of behaving monkeys evoked by microstimulation in the cerebellar nuclei.

Coherent 20-35 Hz (beta) oscillations are a prominent feature of activity in primary motor cortex and muscles of monkeys and humans performing voluntary movements. We found that coherent beta oscillations are also present in the cerebellar nuclei (CN). Two monkeys were operantly conditioned to perform a wrist flexion/extension step-tracking task while we recorded neuronal activity or microstimulated in CN and recorded EMG activity from forelimb muscles. Coherent beta oscillations were found between discharges of some CN neurons and tonically active shoulder, elbow and wrist/finger flexion and extension muscles. Similarly, localized microstimulation pulses in CN evoked transient beta oscillations in widespread forelimb muscles. We conclude that coherent motor system beta oscillations are present in CN and that CN may be an important nodal point for the generation and/or propagation of beta oscillations throughout the motor system.

Arborisation and termination of single motor thalamocortical axons in the rat

The aim of this study was to examine the arborisations and terminations of individual thalamocortical axons in the motor system of the rat. Small, extracellular injections of an anterograde tracer (dextran‐biotin) were made into the ventrolateral (VL) or ventral posterolateral (VPL) thalamic nuclei to label thalamocortical projections. Eleven motor axons and one somatosensory axon were reconstructed through serial sections just rostral from the injection site to their terminations in sensorimotor cortex. The smallest arbor arising from a single motor axon extended approximately 0.9 mm rostrocaudal and 0.9 mm mediolateral, the largest extended 3.9 mm rostrocaudal and 1.0 mm mediolateral. In some cases, two distinct plexuses of terminals were formed by an axon. In addition, motor axons formed terminals in cortical layer V only or in layers I, III, and V. By contrast (and in keeping with previous reports), the somatosensory axon formed a single plexus of terminals in layer IV of the cortex that extended approximately 0.3 mm rostrocaudal and 0.4 mm mediolateral. It is concluded that individual motor thalamocortical neurones are in a position to influence much more widespread cortical regions than somatosensory thalamocortical neurones. J. Comp. Neurol. 396:121–130, 1998.

Activity‐dependent regulation of the dopamine phenotype in substantia nigra neurons

J. Neurochem. (2012) 121, 497–515.