title: The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?
abstract: BACKGROUND
  Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system.
  
  
  OBJECTIVE
  To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy.
  
  
  METHODS
  We searched PubMed articles for the terms "absence epilepsy", "T-type voltage-sensitive calcium channels", "α2δ subunit", "ducky mice", "pregabalin", "gabapentin", "thrombospondins", and included papers focusing this Review's scope.
  
  
  RESULTS
  We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α 2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network.
  
  
  CONCLUSIONS
  We speculate on the possibility that the thrombospondin/α2 δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.
authors.affiliation: I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Celli
authors.affiliation: I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Santolini
authors.affiliation: Departments of Neurosciences, Mental Health and Sensory Organs, Experimental Medicine, and Physiology and Pharmacology, University Sapienza, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guiducci
authors.affiliation: Donders Centre for Cognition, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen. Netherlands.
authors.forename: Gilles
authors.initials: G
authors.lastname: van Luijtelaar
authors.affiliation: Departments of Neurosciences, Mental Health and Sensory Organs, Experimental Medicine, and Physiology and Pharmacology, University Sapienza, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Parisi
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.affiliation: I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: University of Lincoln, School of Pharmacy, Lincoln, United Kingdom.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Ngomba
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza, Piazzale Aldo Moro, 5, 00185 Rome, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D019699:Thrombospondins / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D019699:Thrombospondins
keywords: T-type voltage-sensitive Ca2+ channels; absence epilepsy; ducky mice; gabapentin; non-T-type voltage-sensitive Ca2+ channels; pregabalin; thrombospondins; α2δ subunit