Intrinsic epileptogenicity of dysplastic cortex: Converging data from experimental models and human patients

Abstract

SUMMARYFocal cortical dysplasia (FCD) is a brain malformation associated with particularly severe drugresistant epilepsy that often requires surgery for seizure control. The molecular basis for such enhanced propensity to seizure generation in FCD is not as yet elucidated. To investigate cellular and molecular bases of epileptogenic mechanisms and possible effect of severe epilepsy on the malformed cortex we have here performed a parallel analysis of a rat model of acquired cortical dysplasia previously established in our laboratory, i.e., the methylazoxymethanol/pilocarpine (MAM-PILO) rats, and surgical samples from patients with type IIB FCD.Data from the MAM-PILO rat model and human FCD samples reveal in both conditions: (1) that status epilepticus (SE) and/or seizures can further modify the cellular and molecular settings of the malformed cortex; (2) excitation/inhibition imbalance, and dysregulation of the N-methyl-D-aspartate/ membrane-associated guanylate kinase (NMDA/MAGUK) expression; (3) activation of cell death in neurons and glia. The data therefore highlight the mechanistic relevance of glutamate/ NMDA hyperactivation in FCD epileptogenesis and suggest that epilepsy is a pathologic process capable of affecting structure and function of both neurons and glia.

Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex

“…Our results suggest that the increased excitability after both types of pathophysiological events was caused by an increase in NMDA and AMPA/kainate receptor dependent glutamatergic neurotransmission. Enhancement of NMDA (Battaglia et al, 2013, Telfeian and Connors, 1999) and AMPA (Alefeld et al, 1998) receptors neurotransmission are well described causes of epileptogenicity in young animals. The AMPA antagonist CNQX applied with D-APV allowed the suppression of virtually all events and this confirms that both NMDA and AMPA/kainate receptors are largely responsible for the incidence of epileptiform activity as already described independently of the treatment (Sun et al, 2004).…”

Basic Mechanisms of Epileptogenesis in Pediatric Cortical Dysplasia

“…In particular, dyslamination and the presence of immature, misoriented, and hypertrophic pyramidal neurons with or without tortuous processes could certainly lead to aberrant connectivity. In CD type II, the dysplastic neurons are postulated as essential pathogenetic elements [86] and the source of ictal discharges [20]. Of the different dysplastic cells, cytomegalic pyramidal neurons are more likely to be epileptogenic, while balloon cells are not epileptogenic [85].…”

A New Rat Model of Epileptic Spasms Based on Methylazoxymethanol-Induced Malformations of Cortical Development

“…Depending on MCDs severity and pattern, epilepsies may manifest at almost any developmental stage from newborns to adults and some patients with MCDs present with epileptic spasms (3, 4). Several animal models have been generated to reproduce the pathologic characteristics of human MCDs for the investigation of the causal relationship between specific dysplastic lesions and functional abnormalities (5, 6). One such model is prenatal methylazoxymethanol (MAM)-induced MCDs.…”