Abstract
Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits.
Highlights
Brain tumor patients commonly present with epileptic seizures
Using a clinically relevant glioma model, in which patient-derived xenolines were implanted into scid mice, we show that the peritumoral cortex (PTC) within 0.6 mm of tumor is plagued by excitotoxic neuronal cell death fast spiking interneurons (FSNs)
Since ~80% of PV+ interneurons are surrounded by perineuronal nets (PNNs), which is identified by Wisteria Floribunda Agglutinin (WFA) staining (WFA+), and virtually all PNN-surrounded neurons in the cerebral cortex are FSNs14,19, both PV and WFA were used as a marker to identify FSNs (Supplementary Fig. 1a, b)
Summary
Brain tumor patients commonly present with epileptic seizures. We show that tumorassociated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and decreased GABA release. Rather an additional loss of GABAergic inhibition is required with at least two suspected contributors; the peritumoral brain shows ~35% reduction in the density of fast spiking GABAergic interneurons[3] and the remaining GABAergic neurons show a significantly reduced inhibitory potential. The latter may be secondary to a change in the cell’s chloride (Cl−) equilibrium potential[3,5] rendering GABA currents less inhibitory. PNNs constituents are substrates for matrix degrading enzymes including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), which are known to be released from gliomas[21], and may be subject to degradation by invading tumor cells
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