Aberrant neuronal connectivity in the cortex drives generation of seizures in rat absence epilepsy

Using a genetic model of absence epilepsy in the rat, Studer et al. show that increased structural connectivity of cortical neurons contributes to the increased neuronal synchronization associated with the generation of absence seizures. Absence epilepsy belongs to genetic epilepsies and is characterized by recurrent generalized seizures that are concomitant with alterations of consciousness and associated with cognitive comorbidities. Little is known about the mechanisms leading to occurrence of epileptic seizures (i.e. epileptogenesis) and, in particular, it remains an open question as to whether neuronal hypersynchronization, a key feature in seizure initiation, could result from aberrant structural connectivity within neuronal networks endowing them with epileptic properties. In the present study, we addressed this question using a genetic model of absence epilepsy in the rat where seizures initiate in the whisker primary somatosensory cortex (wS1). We hypothesized that alterations in structural connectivity of neuronal networks within wS1 contribute to pathological neuronal synchronization responsible for seizures. First, we used rabies virus-mediated retrograde synaptic tracing and showed that cortical neurons located in both upper- and deep-layers of wS1 displayed aberrant and significantly increased connectivity in the genetic model of absence epilepsy, as highlighted by a higher number of presynaptic partners. Next, we showed at the functional level that disrupting these aberrant wS1 neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both the synchronization and seizure power of wS1 neurons, as revealed by in vivo local field potential recordings with multichannel probes. Taken together, our data provide for the first time strong evidence that increased structural connectivity patterns of cortical neurons represent critical pathological substrates for increased neuronal synchronization and generation of absence seizures.

Automated summary

In this study, the researchers used a genetic model of absence epilepsy in rats to investigate the role of structural connectivity of cortical neurons in the generation of absence seizures. The results showed that increased structural connectivity contributes to the increased neuronal synchronization associated with absence seizures. This study provides strong evidence that aberrant structural connectivity patterns of cortical neurons are critical pathological substrates for increased neuronal synchronization and the generation of absence seizures.