Glioma-induced peritumoral hyperexcitability in a pediatric glioma model.

Lata Chaunsali,Bhanu P Tewari,Allison Gallucci,Andrew Savoia,Susan L Campbell,Emily G Thompson,Noah Feld

doi:10.14814/phy2.14567

Abstract

Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma‐related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient‐derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons.

Highlights

Gliomas are primary brain tumors derived from cells of the glial lineage
Using an adult glioma model, we previously reported hyperexcitability in peritumoral neurons leading to spontaneous epileptic seizures (Buckingham et al, 2011)
We created two pediatric glioma models to examine the impact of pediatric glioma cells on the function of neurons in the immature cortex

Summary

| INTRODUCTION

Wilmshurst, Berg, Lagae, Newton, & Cross, 2014). They are the primary cause of years of potential life lost in children, accounting for 31% of potential life lost (de Blank et al, 2015). The tumor type, location, genetics, epigenetics, and microenvironment have been implicated as risk factors (Weller, Stupp, & Wick, 2012) In reference to the latter, there is a stark difference in the tumor microenvironment of pediatric and adult glioma patients, which could affect neuronal changes involved in seizure development. It is characterized by distinct cortical neuronal network activity that is highly susceptible to synchronized activity (Sanchez & Jensen, 2001) In early development, both intrinsic cellular properties and network architecture contribute to this feature of the immature CNS, which causes seizure incidence to be at its highest in the first year of life, and these seizures are more resistant to antiepileptic drugs (AEDs; Nardou, Ferrari, & Ben-Ari, 2013). The passive neuronal properties of immature neurons such as depolarized resting membrane potential, high input resistance, and

Key points summary

| RESULTS

| DISCUSSION

| Ethical approval