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
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.