Brain excitability and synaptic plasticity in experimental epilepsy.

Epilepsy is a chronic neurological disorder characterized by repeated seizures, i.e. periods of paroxysmal brain activity commonly attributed to an imbalance between excitatory and inhibitory neuronal pathways. Understanding the cellular and molecular mechanisms underlying brain hyperexcitability is of central importance in epilepsy research. Here, I report two separate studies based on experimental mouse models of epilepsy aimed at: 1) detecting and quantifying mechanisms of synaptic plasticity in an epileptic encephalopathy syndrome; and 2) describing the pattern of expression of an ATP receptor associated with epileptogenesis in a model of temporal lobe epilepsy, as well as understanding its contribution to the disorder. Study 1. An inbred mouse strain, the A/J JAX, has been shown to present repeated spike-wave discharges (SWD) during slow-wave sleep, resembling an insidious, drug-resistant epileptic syndrome of childhood. We carried out, in both affected and control (A/J OLA) mice, in-vivo electrophysiological recordings and histological analyses of brain tissue, aimed at detecting and quantifying both excitatory and inhibitory synaptic contacts, with and without extended training in a motor learning task. Unlike OLA controls, all JAX mice examined at a young age were affected by spontaneously occurring SWDs and failed to improve in the performance of the task after training. In older JAX mice, SWDs were instead absent, in line with the progressive disappearance of discharges described over the years in human patients. Compared to the OLA group, JAX mice showed higher numbers of glutamatergic synapses in the cerebral cortex as well as a lower number of GABAergic contacts, a pattern that was modified by motor training, with differential effects on the two strains. Study 2. Temporal lobe epilepsy is the most frequent type of epilepsy in adult patients and the most common cause of drug-resistant seizures. The P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability and has been postulated as a treatment target for epilepsy. Its inhibition can, however, produce both pro- and anti-seizure effects. To understand the basis for these opposing actions, we generated mice lacking the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy- 1-Cre). Mice lacking P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy and a molecular profile characteristic of an anti-inflammatory phenotype in microglia. In contrast, mice lacking P2X7R in neurons showed more severe evoked seizures and developed more frequent spontaneous seizures. Our results provide an explanation for the opposing actions of P2X7R in epilepsy and pave the way for investigating which neuronal subtypes are involved in this mechanism.