title: Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice.
abstract: Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca(2+)] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory-inhibitory balance in FHM1.
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, Italy.
authors.forename: Dania
authors.initials: D
authors.lastname: Vecchia
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, Italy.
authors.forename: Angelita
authors.initials: A
authors.lastname: Tottene
authors.affiliation: Department of Human Genetics and Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, Italy. Electronic address: daniela.pietrobon@unipd.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietrobon
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D005680:gamma-Aminobutyric Acid; C105656:CACNA1A protein, human
keywords: Channelopathy; Excitatory–inhibitory balance; Fast-spiking interneuron; Knockin mouse model; Migraine; calcium channel, inhibitory synaptic transmission