Roberta Celli, Ines Santolini, Michela Guiducci, Gilles van Luijtelaar, Pasquale Parisi, Pasquale Striano, Roberto Gradini, Giuseppe Battaglia, Richard T. Ngomba and Ferdinando Nicoletti* Pages 918 - 925 ( 8 )
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. Conclusion: 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.
α2δ subunit, T-type voltage-sensitive Ca2+ channels, non-T-type voltage-sensitive Ca2+ channels, ducky mice, pregabalin, gabapentin, absence epilepsy, thrombospondins.
I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), Departments of Neurosciences, Mental Health and Sensory Organs, Experimental Medicine, and Physiology and Pharmacology, University Sapienza, Rome, Donders Centre for Cognition, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Departments of Neurosciences, Mental Health and Sensory Organs, Experimental Medicine, and Physiology and Pharmacology, University Sapienza, Rome, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genova, I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), I.R.C.C.S. Neuromed, Neuropharmacology Unit, Pozzilli, (IS), University of Lincoln, School of Pharmacy, Lincoln, Department of Physiology and Pharmacology, University Sapienza, Piazzale Aldo Moro, 5, 00185 Rome