Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

Abstract

<jats:title>Abstract</jats:title><jats:p>Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we followed glioma progression in awake Thy1-GCaMP6f mice using in-vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring new biomarkers and therapeutic targets.</jats:p><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="simple"><jats:list-item><jats:label>-</jats:label><jats:p>Glioma disrupts neural synchrony between bilateral cortical regions.</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>WFOM reveals frequent interictal discharges and seizures during glioma progression.</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>Tumor development is accompanied by local changes in neurovascular coupling.</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>Altered neurovascular coupling drives hypoperfusion of the tumor during seizures.</jats:p></jats:list-item></jats:list></jats:p></jats:sec>

Wheels Within Wheels: Theory and Practice of Epileptic Networks

“…Unfortunately, there are few established epilepsy models that have been shown to reproduce the large-scale network effects seen in humans, particularly for focal neocortical syndromes. Existing work includes a focal brain tumor model explored during spontaneous epileptiform activity and seizures using widefield GCaMP imaging, 34 a post-stroke epilepsy model in which thalamic connectivity with the seizure focus site in primary somatosensory cortex was demonstrated to have an important role in seizure generation, 35 and studies of the effects of optogenetic cell-type specific activation on pilocarpine-induced seizures, 36,37 with stimulation of interneurons in the fastigial nucleus of the cerebellum preventing seizures in a mouse pilocarpine model. 38 As these models all have important limitations in terms of relevance for patients with chronic focal epilepsy syndromes, there is an urgent need for further work in this area.…”

Elongation Inhibitors do not Prevent the Release of Puromycylated Nascent Polypeptide Chains from Ribosomes

“…We utilized murine RiboTag glioma cells (Montgomery et al, 2019) to test the feasibility of eL22-HA/Puro PLA in vitro. After pretreatment with emetine and brief puromycin labeling, we fixed cells and analyzed anti-puromycin immunofluorescence (IF) and eL22-HA/Puro PLA in parallel ( Figure 1C, see Figure 1 -figure supplement 3 for summary statistics and testing).…”

“…The murine RiboTag glioma line expressing eL22-HA was previously described (Montgomery et al, 2019). U87 human glioma cells, murine RiboTag glioma cells, and HEK-293FT cells were cultured in Dulbecco's modified eagle medium (DMEM, Life Technologies, catalog #11965118) supplemented with 10% fetal bovine serum (FBS, Life Technologies, catalog #16000044).…”