Role of different voltage-gated Ca²⁺channels in cortical spreading depression: Specific requirement of P/Q-type Ca²⁺channels

The Complex Relationship Between Epilepsy and Headache and the Concept of Ictal Epileptic Headache

“…With regard to the concept of "cortex dys-excitability" in migraine subjects, new advances now support this point of view (Berger et al 2008;Fabricius et al 2008;Tottene et al 2009Tottene et al , 2011Faragauna et al 2010;De Souza et al 2011). Indeed, if we consider the specific polysynaptic inhibitory sub-circuit involving fast-spiking (FS) inter-neurons and pyramidal cells (PC) that have been investigated in FHM1 mice (Berger et al 2008;Fabricius et al 2008;Tottene et al 2009Tottene et al , 2011Faragauna et al 2010;De Souza et al 2011), the gain in function following glutamate release at the recurrent synapses between pyramidal cells would certainly increase network excitation; by contrast, the gain in function following glutamate release at the PC-FS synapses would lead to enhanced recruitment of inter-neurons and enhanced inhibition.…”

“…Moreover, the onset of both CSD and that of the epileptic seizure may facilitate each other (Berger et al 2008;Fabricius et al 2008;Zhang et al 2011;Parisi et al 2012b), with these two phenomena possibly being triggered by more than one pathway converging upon the same destination: depolarization and hyper-synchronization (Parisi et al 2008(Parisi et al , 2012aParisi 2009a,b;Belcastro et al 2011a, b;Ghadiri et al 2012). The triggering causes, which may be environmental or individual (whether genetically determined or not), result in a flow of ions that mediate CSD through neuronal and glial cytoplasmic bridges rather than through interstitial spaces, as instead usually occurs in the spreading of epileptic seizures (Gigout et al 2006;Parisi et al 2008;Parisi 2009b;Tamura et al 2011;Tottene et al 2009Tottene et al , 2011. As mentioned above, the threshold required for the onset of CSD is likely to be lower than that required for the epileptic seizure.…”

“…Both migraine and epilepsy have an important genetic component, with strong evidence pointing to a shared genetic basis between headache and epilepsy emerging from clinical/EEG and genetic studies on Familial Hemiplegic Migraine (FHM) (Haglund and Schwartzkroin 1990;De Fusco et al 2003;Vanmolkot et al 2003;Kors et al 2004;Dichgans et al 2005;De Vries et al 2009;Tottene et al 2009Tottene et al , 2011Gambardella and Marini 2009;Van Den Maagdenberg et al 2010;Riant et al 2010;Pietrobon 2010;Uchitel et al 2012). Errors in the same gene may be associated with migraine in some cases and with epilepsy in others.…”

“…Indeed, since hypo-and hyper-excitation in migraine occur sequentially as rebound phenomena (during a spreading depression), the term "dys-excitability" may better describe migraine pathophysiology than hyper-excitability (Somjen 2001;Berger et al 2008;Tottene et al 2009Tottene et al , 2011Fabricius et al 2008;Parisi et al 2012a, b). Cortical Spreading Depression (CSD), which may be considered the link between headache and epilepsy (Moskowitz et al 1993;Bolay et al 2002;Ayata et al 2006;Ayata 2010;Parisi et al 2008a, b;Parisi 2009a, b;Eikermann-Haerter & Ayata 2010;Belcastro et al 2011a, b;Zhang et al 2011;Parisi et al 2012a;Ghadiri et al 2012), is characterized by a slowly propagating wave of sustained strong neuronal depolarization that generates transient intense spike activity, followed by neural suppression, which may last for minutes.…”

“…Indeed, if we consider the specific polysynaptic inhibitory sub-circuit involving fast-spiking (FS) inter-neurons and pyramidal cells (PC) that have been investigated in FHM1 mice (Berger et al 2008;Fabricius et al 2008;Tottene et al 2009Tottene et al , 2011Faragauna et al 2010;De Souza et al 2011), the gain in function following glutamate release at the recurrent synapses between pyramidal cells would certainly increase network excitation; by contrast, the gain in function following glutamate release at the PC-FS synapses would lead to enhanced recruitment of inter-neurons and enhanced inhibition. Although this analysis is restricted to a specific sub-circuit, it does raise the important point that the differential effect of FHM1 mutations on excitatory and inhibitory neurotransmission may produce over-excitation in certain brain conditions, while leaving the excitation-inhibition balance within physiological limits in others.…”