Building Up Absence Seizures in the Somatosensory Cortex: From Network to Cellular Epileptogenic Processes

Abstract

The epileptogenic processes leading to recurrent seizures in Genetic Epilepsies are largely unknown. Using the Genetic Absence Epilepsy Rat from Strasbourg, we investigated in vivo the network and single neuron mechanisms responsible for the early emergence of epileptic activity. Local field potential recordings in the primary somatosensory cortex (SoCx), from the second post-natal week to adulthood, showed that immature cortical discharges progressively evolved into typical spike-and-wave discharges following a 3-step maturation process. Intracellular recordings from deep-layer SoCx neurons revealed that this maturation was associated with an age-dependent increase in cortical neurons intrinsic excitability, combining a membrane depolarization and an enhancement of spontaneous firing rate with a leftward shift in their input-output relation. These cellular changes were accompanied by a progressive increase in the strength of the local synaptic activity associated with a growing propensity of neurons to generate synchronized oscillations. Chronic anti-absence treatment before the occurrence of mature cortical discharges did not alter epileptogenesis or the drug efficiency at adulthood. These findings demonstrate that recurrent absence seizures originate from the progressive acquisition of pro-ictogenic properties in SoCx neurons and networks during the post-natal period and that these processes cannot be interrupted by early anti-absence treatment.

Sensory coding is impaired in rat absence epilepsy

“…3 weeks in GAERS) (Jarre et al . ), the increase of PV+ cells in GAERS could result from the repetition of SWDs. This suggests that the increased density of inhibitory interneurons could rather be a consequence of the repetition of seizures than its cause.…”

Early reduced dopaminergic tone mediated by D3 receptor and dopamine transporter in absence epileptogenesis

“…Hence, the recurrence of SWDs may aggravate the imbalance in dopaminergic tone by maintaining increased D3R expression and DAT activity, therefore reducing overfluctuations of DA levels. This hypothesis is further supported by the progressive increase of SWD occurrence and duration during the first 3‐4 months of life in GAERSs . A decreased dopaminergic tone during this period may thus contribute to the progressive aggravation of seizures.…”

“…In this model, low‐amplitude epileptiform oscillations first occur in the somatosensory cortex at postnatal day (P)14 and progressively evolve as spike‐and‐wave discharges (SWDs)—that is, the electrophysiological hallmark of absence seizures—which are recorded not before P25 . The number of spike‐and‐wave patterns per discharge and the duration of discharges then progressively increase, to stabilize in adults after P90 …”

Long‐term negative impact of an inappropriate first antiepileptic medication on the efficacy of a second antiepileptic medication in mice

“…Immediately after the first (this initial) EEG recording, mice were treated daily for 2 weeks with either VPA (200 mg/kg/day; Aguettant, Lyon, France, batch number 4202475), ESM (200 mg/kg/day; Sigma‐Aldrich France, Saint‐Quentin‐Fallavier, France, batch number 129K1342), or VGB (500 mg/kg/day; Sanofi‐Aventis, Gentilly, France, batch number 7544) dissolved in saline solution (0.9%). These doses were chosen based on previous research and what is typically used in seizure models and experimental epilepsy in rats as well as in mice . Serum drug levels were not assessed in the present study.…”