Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice
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 a...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114001533 |
| _version_ | 1823925092581638144 |
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| author | Dania Vecchia Angelita Tottene Arn M.J.M. van den Maagdenberg Daniela Pietrobon |
| author_facet | Dania Vecchia Angelita Tottene Arn M.J.M. van den Maagdenberg Daniela Pietrobon |
| author_sort | Dania Vecchia |
| collection | DOAJ |
| description | 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 [Ca2+] 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. |
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| id | doaj.art-b510692d7c3c464f9a010545e7f49ebd |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T20:03:26Z |
| publishDate | 2014-09-01 |
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| series | Neurobiology of Disease |
| spelling | doaj.art-b510692d7c3c464f9a010545e7f49ebd2022-12-21T22:18:24ZengElsevierNeurobiology of Disease1095-953X2014-09-0169225234Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine miceDania Vecchia0Angelita Tottene1Arn M.J.M. van den Maagdenberg2Daniela Pietrobon3Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, ItalyDepartment of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, ItalyDepartment of Human Genetics and Neurology, Leiden University Medical Centre, Leiden, The NetherlandsDepartment of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, Italy; Corresponding author at: Dept. of Biomedical Sciences, University of Padova, V.le G. Colombo 3, 35121 Padova, Italy.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 [Ca2+] 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.http://www.sciencedirect.com/science/article/pii/S0969996114001533MigraineFast-spiking interneuronKnockin mouse modelChannelopathyExcitatory–inhibitory balance |
| spellingShingle | Dania Vecchia Angelita Tottene Arn M.J.M. van den Maagdenberg Daniela Pietrobon Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice Neurobiology of Disease Migraine Fast-spiking interneuron Knockin mouse model Channelopathy Excitatory–inhibitory balance |
| title | Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice |
| title_full | Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice |
| title_fullStr | Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice |
| title_full_unstemmed | Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice |
| title_short | Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice |
| title_sort | mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in cav2 1 knockin migraine mice |
| topic | Migraine Fast-spiking interneuron Knockin mouse model Channelopathy Excitatory–inhibitory balance |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114001533 |
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