Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice.
Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(V)2.1 (P/Q-type) Ca(2+) channels. Knockin mice carrying a FHM1 mutation show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 mice. We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses. Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation. The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine.
Tottene
Angelita
A
Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, Viale G. Colombo 3, Padua, Italy.
Conti
Rossella
R
Fabbro
Alessandra
A
Vecchia
Dania
D
Shapovalova
Maryna
M
Santello
Mirko
M
van den Maagdenberg
Arn M J M
AM
Ferrari
Michel D
MD
Pietrobon
Daniela
D
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000235:genetics; D055592:Biophysical Phenomena; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005973:Glutamine / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000166:cytology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D001120:Arginine; D002118:Calcium; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D005973:Glutamine