title: Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits.
abstract: Absence epilepsy is a common disorder that arises in childhood and can be refractory to medical treatment. Single genetic mutations in mice, at times found in patients with absence epilepsy, provide the unique opportunity to bridge the gap between dysfunction at the genetic level and pathological oscillations within the thalamocortical circuit. Interestingly, unlike other forms of epilepsy, only genes related to ion channels have so far been linked to absence phenotypes. Here, we delineate a paradigm which attempts to unify the various monogenic models based on decades of research. While reviewing the particular impact of these individual mutations, we posit a framework involving fast feedforward disinhibition as one common mechanism that can lead to increased tonic inhibition in the cortex and/or thalamus. Enhanced tonic inhibition hyperpolarizes principal cells, deinactivates T-type calcium channels, and leads to reciprocal burst firing within the thalamocortical loop. We also review data from pharmacologic and polygenic models in light of this paradigm. Ultimately, many questions remain unanswered regarding the pathogenesis of absence epilepsy.
authors.affiliation: Department of Neurology, Developmental Neurogenetics Laboratory, Baylor College of Medicine Houston, TX, USA. Electronic address: atul.maheshwari@bcm.edu.
authors.forename: Atul
authors.initials: A
authors.lastname: Maheshwari
authors.affiliation: Department of Neurology, Developmental Neurogenetics Laboratory, Baylor College of Medicine Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: jnoebels@bcm.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology*; D004832:Epilepsy, Absence / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008957:Models, Genetic; D009434:Neural Pathways / Q000503:physiopathology*; D013788:Thalamus / Q000503:physiopathology*
keywords: T-type calcium channels; corticothalamic; disinhibition; feedforward inhibition; gene; ion channel; tonic inhibition