Glial Biology in Health, Disease, and Cancer Center, Virginia Tech Carilion Research Institute, 2 Riverside Cir., Roanoke, VA, 24016, USA.
Department of Animal and Poultry Sciences, Virginia Tech, 3460 Litton Reaves Hall, Blacksburg, VA, 24061, USA.
Nat Commun. 2018 Nov 9;9(1):4724. doi: 10.1038/s41467-018-07113-0.
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.
脑肿瘤患者通常会出现癫痫发作。我们表明，肿瘤相关的癫痫发作是由于肿瘤周围快速放电中间神经元（FSNs）的整体缺失以及剩余的 FSNs 的放电率显著降低而导致的 GABA 能抑制受损的结果。放电减少是由于围绕 FSN 的周围神经毡（PNNs）的降解。我们表明，PNNs 降低了 FSNs 的特定膜电容，使其能够以超生理频率发射动作电位。肿瘤释放的蛋白水解酶降解 PNNs，导致膜电容增加、放电减少，从而导致 GABA 释放减少。这些研究揭示了 PNNs 作为一种静电绝缘体的先前未知作用，它降低了特定的膜电容，在功能上类似于轴突周围的髓鞘，从而使 FSNs 能够超过生理放电率。PNNs 的破坏也可能解释了其他形式癫痫中的兴奋-抑制失衡，通过蛋白水解抑制保护 PNNs 可能提供治疗益处。
