Glioma-Induced Alterations in Neuronal Activity and Neurovascular Coupling during Disease Progression

Abstract

SUMMARY 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 follow 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 gradually decreases in glioma-infiltrated cortical regions, while neurovascular coupling becomes progressively disrupted compared to uninvolved cortex. Over time, mice develop diverse patterns of high amplitude discharges and eventually generalized seizures that appear to originate at the tumors’ infiltrative margins. Interictal and seizure events exhibit positive neurovascular coupling in uninfiltrated cortex; however, glioma-infiltrated regions exhibit disrupted 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 novel biomarkers and therapeutic targets.

Perampanel Add-on to Standard Radiochemotherapy in vivo Promotes Neuroprotection in a Rodent F98 Glioma Model

“…Interictal events are known to arise during glioma progression and are a subclinical marker of epilepsy. A recently published study suggests that an increasing frequency of interictal events may be associated with progressive neurologic impairment in glioma (Montgomery et al, 2020). The ex vivo presence of an glioma-associated epileptic phenotype is consistent with previous reports on resected human tissue (Köhling et al, 2006) and animal glioma models based on human genetic alterations (Hatcher et al, 2020).…”

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 -source data 1 for summary statistics and testing).…”

“…The murine RiboTag glioma line expressing eL22-HA was a gift from the laboratory of Dr. Peter Canoll and has been previously described (Montgomery et al, 2019). Briefly, gliomas were generated by injection of PDGFA-IRES-Cre expressing retrovirus into subcortical white matter of mice harboring floxed p53, RiboTag, and stop-flox mCherry-luciferase alleles.…”

Single Unit Analysis and Wide-Field Imaging Reveal Alterations in Excitatory and Inhibitory Neurons in Glioma

“…This allowed us to interrogate the spatiotemporal behavior of both putative pyramidal cells and PV interneurons in a diffusely infiltrating model of glioma. Moreover, this approach provided an electrophysiologic correlate for the GCaMP fluctuations observed in longitudinal in vivo imaging of this model 13 . In agreement with prior studies, our ex vivo acute tumor-bearing slices demonstrated increased excitability 4, 7, 12, 17, 42 and decreased FS cell firing 3 without significant increases in pyramidal cell activity.…”

“…These findings may have implications for the clinical course of patients with diffusely infiltrating glioma. Recent reports have shown that aberrant neuronal activity can lead to glioma proliferation through various mechanisms 4, 8–10, 13, 15 . It is thus conceivable that mTOR-mediated restoration of surround inhibition could potentially reduce the spread of such aberrant firing and in turn decrease tumor progression.…”