Cortical and Thalamic PV+ Interneuron Dysfunction in the Pathogenesis of Absence Epilepsy

Abstract

Abstract Childhood absence epilepsy is a common disorder causing recurrent unprovoked episodes of behavioral arrest associated with generalized spike-wave discharges on the electroencephalogram (EEG). The corticothalamic circuit that generates these discharges involves both excitatory neurons and parvalbumin-expressing inhibitory neurons (PV-INs) in both the cortex and thalamus. Corticothalamic PV-INs normally maintain fast feedforward inhibition (FFI), and dysfunction in FFI has been implicated in several drug-induced, monogenic mutant rodent and inbred rat models of absence epilepsy. This dysfunction causes a cascade of molecular events, resulting in the recruitment of increased tonic inhibition, and culminating in synchronous burst firing of the corticothalamic neurons mediated by T-type calcium channels. Recent studies using in vivo two-photon imaging and electrophysiology have shown that absence seizures are associated with reduced activity in most corticothalamic neurons, including PV-INs. Optogenetic and chemogenetic techniques have further revealed that reducing PV-IN activity within this circuit is sufficient to cause absence seizures. Further work to understand the role of PV-IN dysfunction in absence seizures is necessary since up to 30% of patients with absence seizures will not respond to first-line treatment with ethosuximide. Even when ethosuximide is effective, it does not specifically treat the PV-IN dysfunction, which may result in ongoing deficits in attention.