Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Distinct mechanisms of Up state maintenance in the medial entorhinal cortex and neocortex.

The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here, we compared the mechanisms involved in the maintenance of the Up state in the barrel cortex (BC) and mEC using whole cell recordings in acute mouse brain slices. Bath application of an NMDA receptor antagonist abolished Up states in the BC, and reduced the incidence but not the duration of Up states in the mEC. Conversely, blockade of kainate receptors decreased Up state duration in the mEC, but not in the BC. Voltage clamp recordings demonstrated the presence of a non-NMDA glutamate receptor-mediated slow excitatory postsynaptic current, sensitive to the selective kainate receptor antagonist UBP-302, in layer III neurons of the mEC, which was not observed in the BC. Moreover, we found that kainate receptor-mediated currents assist in recovery back to the Up state membrane potential following a current-induced hyperpolarisation of individual cells in the mEC. Finally, we were able to generate Up state activity in a network model of exponential integrate-and-fire neurons only supported by AMPA and kainate receptor-mediated currents. We propose that synaptic kainate receptors are responsible for the unique properties of mEC Up states.