Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation.

It was previously shown that mice with genetic deletion of the neurotrophic factor pleiotrophin (PTN-/-) show enhanced amphetamine neurotoxicity and impair extinction of amphetamine conditioned place preference (CPP), suggesting a modulatory role of PTN in amphetamine neurotoxicity and reward. We have now studied the effects of amphetamine (10mg/kg, 4 times, every 2h) in the striatum of mice with transgenic PTN overexpression (PTN-Tg) in the brain and in wild type (WT) mice. Amphetamine caused an enhanced loss of striatal dopaminergic terminals, together with a highly significant aggravation of amphetamine-induced increase in the number of GFAP-positive astrocytes, in the striatum of PTN-Tg mice compared to WT mice. Given the known contribution of D1 and D2 dopamine receptors to the neurotoxic effects of amphetamine, we also performed quantitative receptor autoradiography of both receptors in the brains of PTN-Tg and WT mice. D1 and D2 receptors binding in the striatum and other regions of interest was not altered by genotype or treatment. Finally, we found that amphetamine CPP was significantly reduced in PTN-Tg mice. The data demonstrate that PTN overexpression in the brain blocks the conditioning effects of amphetamine and enhances the characteristic striatal dopaminergic denervation caused by this drug. These results indicate for the first time deleterious effects of PTN in vivo by mechanisms that are probably independent of changes in the expression of D1 and D2 dopamine receptors. The data also suggest that PTN-induced neuroinflammation could be involved in the enhanced neurotoxic effects of amphetamine in the striatum of PTN-Tg mice

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

[EN] Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3,4,5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.S

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

The role of GABAB in drug addiction.

The GABAergic system is the primary inhibitory regulator of the mesolimbic dopamine system, mediating both natural and drug-induced reward behaviours. The GABAB agonist, baclofen, has been postulated as a potential anti-addiction treatment. However, clinical studies have revealed conflicting results and both anti- and pro-rewarding effects of GABAB system activation have been reported. Thus, a deeper and more refined understanding of GABAB receptor pharmacology is needed. GABAB receptors are obligate heterodimers of GABAB(1) and GABAB(2) subunits and further GABAB(1) subunit isoforms are GABAB(1a) and GABAB(1b). While presynaptic GABAB receptors are likely to contain the GABAB(1a) isoform, postsynaptic GABAB receptors are composed of the GABAB(1b) isoform. Using mice lacking in GABAB(1a) (1a KO) and GABAB(1b) (1b KO) isoforms, we tested the hypothesis that the GABAB receptor isoforms differentially modulate psychomotor and reward behaviours of cocaine and morphine, alcohol intake and social behaviours via distinct neurochemical mechanism. We therefore examined cocaine- and morphine-induced locomotion stimulation, sensitisation and conditioned place preference (CPP) as well as alcohol intake. The 3-chambered box was utilised to investigate social behaviours. Cocaine and morphine enhanced the locomotor activity in 1a KO mice but not in 1b KO and WT mice. However, cocaine- and morphine-induced CPP was unaffected by either isoform deletion. Conversely, while WT and 1a KO mice extinguished alcohol preference during withdrawal, this was not seen in 1b KO mice. Finally, 1a KO mice exhibited higher social novelty preference and striatal oxytocin receptor levels compared to WT and 1b KO mice. These results reveal that presynaptic preferring GABAB(1a) receptors selectively modulate the psychomotor effects of cocaine and morphine as well as social novelty, most likely by inhibiting dopaminergic transmission. Conversely, the postsynaptic GABAB(1b) receptors may play a larger role in alcohol addiction. We conclude that targeting GABAB receptor isoforms may constitute an effective approach to drug addiction treatmen

The role of GABAB in drug addiction.

The GABAergic system is the primary inhibitory regulator of the mesolimbic dopamine system, mediating both natural and drug-induced reward behaviours. The GABAB agonist, baclofen, has been postulated as a potential anti-addiction treatment. However, clinical studies have revealed conflicting results and both anti- and pro-rewarding effects of GABAB system activation have been reported. Thus, a deeper and more refined understanding of GABAB receptor pharmacology is needed. GABAB receptors are obligate heterodimers of GABAB(1) and GABAB(2) subunits and further GABAB(1) subunit isoforms are GABAB(1a) and GABAB(1b). While presynaptic GABAB receptors are likely to contain the GABAB(1a) isoform, postsynaptic GABAB receptors are composed of the GABAB(1b) isoform. Using mice lacking in GABAB(1a) (1a KO) and GABAB(1b) (1b KO) isoforms, we tested the hypothesis that the GABAB receptor isoforms differentially modulate psychomotor and reward behaviours of cocaine and morphine, alcohol intake and social behaviours via distinct neurochemical mechanism. We therefore examined cocaine- and morphine-induced locomotion stimulation, sensitisation and conditioned place preference (CPP) as well as alcohol intake. The 3-chambered box was utilised to investigate social behaviours. Cocaine and morphine enhanced the locomotor activity in 1a KO mice but not in 1b KO and WT mice. However, cocaine- and morphine-induced CPP was unaffected by either isoform deletion. Conversely, while WT and 1a KO mice extinguished alcohol preference during withdrawal, this was not seen in 1b KO mice. Finally, 1a KO mice exhibited higher social novelty preference and striatal oxytocin receptor levels compared to WT and 1b KO mice. These results reveal that presynaptic preferring GABAB(1a) receptors selectively modulate the psychomotor effects of cocaine and morphine as well as social novelty, most likely by inhibiting dopaminergic transmission. Conversely, the postsynaptic GABAB(1b) receptors may play a larger role in alcohol addiction. We conclude that targeting GABAB receptor isoforms may constitute an effective approach to drug addiction treatmen

Erbb4 deletion from inhibitory interneurons causes psychosis-relevant neuroimaging phenotypes

BACKGROUND AND HYPOTHESIS: Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA a5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. STUDY DESIGN: Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. RESULTS: Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. CONCLUSIONS: These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species