The role of the dopamine D4 receptor in modulating state-dependent gamma oscillations

Rhythmic oscillations in neuronal activity display variations in amplitude (power) over a range of frequencies. Attention and cognitive performance correlate with increases in cortical gamma oscillations (40-70Hz) that are generated by the coordinated firing of glutamatergic pyramidal neurons and GABAergic interneurons, and are modulated by dopamine. In the medial prefrontal cortex (mPFC) of rats, gamma power increases during treadmill walking, or after administration of an acute subanesthetic dose of the NMDA receptor antagonist ketamine. Ketamine is also used to mimic symptoms of schizophrenia, including cognitive deficits, in healthy humans and rodents. Additionally, the ability of a drug to modify ketamine-induced gamma power has been proposed to predict its pro-cognitive therapeutic efficacy. However, the mechanism underlying ketamine-induced gamma oscillations is poorly understood. We hypothesized that gamma oscillations induced by walking and ketamine would be generated by a shared mechanism in the mPFC and one of its major sources of innervation, the mediodorsal thalamus (MD). Recordings from chronically implanted electrodes in rats showed that both treadmill walking and ketamine increased gamma power, firing rates, and spike-gamma LFP correlations in the mPFC. By contrast, in the MD, treadmill walking increased all three measures, but ketamine decreased firing rates and spike-gamma LFP correlations while increasing gamma power. Therefore, walking- and ketamine-induced gamma oscillations may arise from a shared circuit in the mPFC, but different circuits in the MD. Recent work in normal animals suggests that dopamine D4 receptors (D4Rs) synergize with the neuregulin/ErbB4 signaling pathway to modulate gamma oscillations and cognitive performance. Consequently, we hypothesized that drugs targeting the D4Rs and ErbB receptors would show pro-cognitive potential by reducing ketamine-induced gamma oscillations in mPFC. However, when injected before ketamine, neither the D4R agonist nor antagonist altered ketamine’s effects on gamma power or firing rates in the mPFC, but the pan-ErbB antagonist potentiated ketamine’s increase in gamma power, and prevented ketamine from increasing firing rates. This indicates that D4Rs and ErbB receptors influence gamma power via distinct mechanisms that interact with NMDA receptor antagonism differently. Our results highlight the value of using ketamine-induced changes in gamma power as a means of testing novel pharmaceutical agents

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children