Gap junctions as modulators of synchrony in Parkinson's disease

Parkinson's disease (PD) patients show abnormal levels of synchrony and low-frequency oscillations in the basal ganglia and the motor cortex. This altered neural activity is often associated with the motor symptoms of PD, but the mechanisms for the emergence of synchrony and oscillations remain debated. We suggest that neural gap junctions in cortex and basal ganglia contribute to this transition in activity. While gap junctions between interneurons of cortex and striatum are well described, we do not know whether they appear in GPe and internal globus pallidus (GPi). Using confocal microscopy, we were able to detect the gap junction protein Cx36 in the human GPe and GPi, which was up-regulated in PD patients. Also the corresponding rat tissue showed Cx36 expression. Dopamine has already been described to modulate the conductance of gap junctions [1], especially also in the rat striatum, where dye coupling was increased after dopamine depleting 6-OHDA lesions [2]. In a conductance-based network model of the basal ganglia, we investigate the effect of gap junctional coupling in GPe and GPi on synchrony. While chemical synapses normally desynchronize the network, gap junctional coupling of sufficient strength is able to synchronize the whole basal ganglia. Also synchronized input from cortex to subthalamic nucleus has impact on synchronization, in particular in the case of numerous gap junctions in GPe. To describe the effect of gap junctional coupling between cortical interneurons on synchronized oscillations in the cortex, we introduce a diffusion term in a mean-field model. For high gap junctional coupling, large-amplitude oscillations of low frequency occur which are absent for low gap junctional coupling. Via the hyperdirect pathway, these oscillations could further synchronize the basal ganglia. We conclude that gap junctions can be a powerful trigger of synchrony in the basal ganglia. Their dependence on dopamine could explain the shifts of synchrony in PD. References 1. Li, H, Zhang, Z, Blackburn, MR, Wang, SW, Ribelayga, CP and O'Brien, J Adenosine and dopamine receptors coregulate photoreceptor coupling via gap junction phosphorylation in mouse retina. (2013) The Journal of Neuroscience, 33(7), 3135-3150. 2. Onn, SP and Grace, AA: Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurons in dopamine-denervated rat striatum recorded in vivo. (1999) Synapse, 33(1):1- 15

Comparative genetic architectures of schizophrenia in East Asian and European populations

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Sparse pallidal connections shape synchrony in a network model of the basal ganglia

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Possible roles of gap junctions in network activity during Parkinson´s disease

Methods:\ud Using immunohistochemistry and confocal imaging, we reconstructed the distribution of Cx36, the major neural connexin, in human post-mortem tissue of the STN, GPe and GPi. Our preliminary analysis included tissue from 6 subjects (2x STN control, 2x STN PD, 1x GPi/e control, 1x GPi/e PD). Assuming that at least a part of the detected Cx36 indicates functional gap junctions, we implemented gap junctions in an existing computational model of the basal ganglia, the Rubin-Terman model including the STN, GPe and GPi.\ud \ud Results:\ud Control tissue from the GPe/i showed punctuate Cx36 labeling, which was absent in a negative control leaving out the primary antibody. PD tissue additionally showed clusters of cells highly expressing Cx36. In the STN, only few spots of Cx36 were visible in control tissues. Their occurrence did not significantly increase in PD tissue. In the Rubin-Terman model (2002/2004) including STN, GPe and GPi, homogeneous gap junction coupling between nearest neighbors inside the GPe/i only slightly influenced the network behavior, unless the gap junction conductance was very high. However, clusters of cells in the GPi/e coupled via gap junctions led to bursting and synchronization, even if the gap junction conductance was comparably low.\ud \ud Conclusions:\ud Clusters of cells coupled via gap junctions seen in the GPi/e of the PD patient could explain the occurrence of bursting and synchronization in the basal ganglia. The modulation of gap junctions by dopamine might be a candidate for the remodeling of neural activity. Our experiments do not provide evidence for the functionality of the detected gap junctions

Pallidal gap junctions-triggers of synchrony in Parkinson's disease?

Item does not contain fulltextAlthough increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin-36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin-36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin-36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin-36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia

Exploiting pallidal plasticity for stimulation in Parkinson’s disease

Objective. Continuous application of high-frequency deep brain stimulation (DBS) often effectively reduces motor symptoms of Parkinson’s disease patients. While there is a growing need for more effective and less traumatic stimulation, the exact mechanism of DBS is still unknown. Here, we present a methodology to exploit the plasticity of GABAergic synapses inside the external globus pallidus (GPe) for the optimization of DBS. Approach. Assuming the existence of spike-timing-dependent plasticity (STDP) at GABAergic GPe–GPe synapses, we simulate neural activity in a network model of the subthalamic nucleus and GPe. In particular, we test different DBS protocols in our model and quantify their influence on neural synchrony. Main results. In an exemplary set of biologically plausible model parameters, we show that STDP in the GPe has a direct influence on neural activity and especially the stability of firing patterns. STDP stabilizes both uncorrelated firing in the healthy state and correlated firing in the parkinsonian state. Alternative stimulation protocols such as coordinated reset stimulation can clearly profit from the stabilizing effect of STDP. These results are widely independent of the STDP learning rule. Significance. Once the model settings, e.g., connection architectures, have been described experimentally, our model can be adjusted and directly applied in the development of novel stimulation protocols. More efficient stimulation leads to both minimization of side effects and savings in battery power

Synchrony in Parkinson’s disease: importance of intrinsic properties of the external globus pallidus

The mechanisms for the emergence and transmission of synchronized oscillations in Parkinson’s disease, which are potentially causal to motor deficits, remain debated. Aside from the motor cortex and the subthalamic nucleus, the external globus pallidus (GPe) has been shown to be essential for the maintenance of these oscillations and plays a major role in sculpting neural network activity in the basal ganglia (BG). While neural activity of the healthy GPe shows almost no correlations between pairs of neurons, prominent synchronization in the β frequency band arises after dopamine depletion. Several studies have proposed that this shift is due to network interactions between the different BG nuclei, including the GPe. However, recent studies demonstrate an important role for the properties of neurons within the GPe. In this review, we will discuss these intrinsic GPe properties and review proposed mechanisms for activity decorrelation within the dopamine-intact GPe. Failure of the GPe to desynchronize correlated inputs can be a possible explanation for synchronization in the whole BG. Potential triggers of synchronization involve the enhancement of GPe-GPe inhibition and changes in ion channel function in GPe neurons

Fatal PML associated with efalizumab therapy: Insights into integrin αLβ2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control