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

Brain. 2022 Feb 9;awab438. doi: 10.1093/brain/awab438. Online ahead of print.

Abstract

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 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. 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 evidenced that cortical neurons located in both upper- and deep-layers of whisker primary somatosensory cortex displayed aberrant and significantly increased connectivity 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 whisker primary somatosensory cortex neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both whisker primary somatosensory cortex neuron synchronization and seizure power, 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.

Keywords: absence epilepsy; neuronal synchronization; rabies virus synaptic tracing; somatosensory cortex; synchrotron microtransections.