Altered functional connectivity and network excitability in a model of cortical dysplasia

Abstract

Focal cortical dysplasias (FCDs) are malformations of cortical development that often result in medically-refractory epilepsy, with greater incidence in the pediatric population. The relation between the deranged cortical morphology of FCD and their epileptogenic activity remains unclear. We used the BCNU animal model of cortical dysplasia to evaluate neuronal and laminar alterations and how these result in altered activity of intracortical networks in an early stage of development. We corroborated the previously-reported morphological anomalies characteristic of the BCNU model, comprising slightly larger and rounder neurons and abnormal cortical lamination. Next, neuronal activity of live cortical slices was evaluated through large field-of-view calcium imaging and their response to a stimulus that leads to cortical hyperexcitability (pilocarpine). Examination of the joint activity of neuronal calcium time series allowed us to identify intracortical communication patterns and their response to pilocarpine. Baseline power density distribution of neurons in the cortex of BCNU-treated animals was different from that from control animals, with the former showing no modulation after stimulus. Moreover, the intracortical communication pattern differed between the two groups, with cortexes from BCNU-treated animals displaying decreased inter-layer connectivity as compared to control animals. Our results indicate that the altered anatomical organization of the cortex of BCNU-treated rats translates into altered functional networks that respond abnormally to a hyperexcitable stimulus, and highlights the role of network dysfunction in the pathophysiology of cortical dysplasia.

Longitudinal Multi-Tensor Analysis of Neocortical Microstructure in an Animal Model of Cortical Dysplasia

“…Afterward, the animals were scanned at 30, 60, 120, and 150 post-natal days with our MRI protocols and processed for histology. BCNU-treated rats did not show any gross phenotypical or behavioral abnormalities compared to the controls and did not present spontaneous seizures, as expected in this animal model (Aquiles et al, 2023;Benardete and Kriegstein, 2002).…”