Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1
Abstract Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies su...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
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| Series: | Molecular Brain |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13041-023-01062-6 |
| _version_ | 1797636623621423104 |
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| author | Stuart M. Cain Sascha R. A. Alles Ray Gopaul Louis-Philippe Bernier Andrew C. Yung Andrew Bauman Yi Yang Glen B. Baker Piotr Kozlowski Brian A. MacVicar Terrance P. Snutch |
| author_facet | Stuart M. Cain Sascha R. A. Alles Ray Gopaul Louis-Philippe Bernier Andrew C. Yung Andrew Bauman Yi Yang Glen B. Baker Piotr Kozlowski Brian A. MacVicar Terrance P. Snutch |
| author_sort | Stuart M. Cain |
| collection | DOAJ |
| description | Abstract Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Cav2.1S218L mutation (S218L). In addition, chronic pregabalin treatment limited subcortical propagation of recurrent spreading depolarization events to the striatum and hippocampus in both wild-type and S218L mice. To examine contributing underlying mechanisms of action of chronic pregabalin, we performed whole-cell patch-clamp electrophysiology in CA1 neurons in ex vivo brain slices from mice treated with chronic pregabalin vs vehicle. In WT mice, chronic pregabalin produced a decrease in spontaneous excitatory postsynaptic current (sEPSC) amplitude with no effect on frequency. In contrast, in S218L mice chronic pregabalin produced an increase in sEPSC amplitude and decreased frequency. These electrophysiological findings suggest that in FHM-1 mice chronic pregabalin acts through both pre- and post-synaptic mechanisms in CA1 hippocampal neurons to elicit FHM-1 genotype-specific inhibitory action. The results highlight the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs. |
| first_indexed | 2024-03-11T12:36:42Z |
| format | Article |
| id | doaj.art-7f60fbce64114253a4fc70c967d52dd5 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-03-11T12:36:42Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-7f60fbce64114253a4fc70c967d52dd52023-11-05T12:32:38ZengBMCMolecular Brain1756-66062023-11-0116111410.1186/s13041-023-01062-6Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1Stuart M. Cain0Sascha R. A. Alles1Ray Gopaul2Louis-Philippe Bernier3Andrew C. Yung4Andrew Bauman5Yi Yang6Glen B. Baker7Piotr Kozlowski8Brian A. MacVicar9Terrance P. Snutch10Michael Smith Laboratories, University of British ColumbiaMichael Smith Laboratories, University of British ColumbiaMichael Smith Laboratories, University of British ColumbiaDjavad Mowafaghian Center for Brain Health, University of British ColumbiaUBC MRI Research Facility, University of British ColumbiaUBC MRI Research Facility, University of British ColumbiaMichael Smith Laboratories, University of British ColumbiaNeurochemical Research Unit, Department of Psychiatry, University of AlbertaUBC MRI Research Facility, University of British ColumbiaDjavad Mowafaghian Center for Brain Health, University of British ColumbiaMichael Smith Laboratories, University of British ColumbiaAbstract Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Cav2.1S218L mutation (S218L). In addition, chronic pregabalin treatment limited subcortical propagation of recurrent spreading depolarization events to the striatum and hippocampus in both wild-type and S218L mice. To examine contributing underlying mechanisms of action of chronic pregabalin, we performed whole-cell patch-clamp electrophysiology in CA1 neurons in ex vivo brain slices from mice treated with chronic pregabalin vs vehicle. In WT mice, chronic pregabalin produced a decrease in spontaneous excitatory postsynaptic current (sEPSC) amplitude with no effect on frequency. In contrast, in S218L mice chronic pregabalin produced an increase in sEPSC amplitude and decreased frequency. These electrophysiological findings suggest that in FHM-1 mice chronic pregabalin acts through both pre- and post-synaptic mechanisms in CA1 hippocampal neurons to elicit FHM-1 genotype-specific inhibitory action. The results highlight the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs.https://doi.org/10.1186/s13041-023-01062-6Spreading depolarizationPregabalinFamilial hemiplegic migraineSpontaneous excitatory postsynaptic currents |
| spellingShingle | Stuart M. Cain Sascha R. A. Alles Ray Gopaul Louis-Philippe Bernier Andrew C. Yung Andrew Bauman Yi Yang Glen B. Baker Piotr Kozlowski Brian A. MacVicar Terrance P. Snutch Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 Molecular Brain Spreading depolarization Pregabalin Familial hemiplegic migraine Spontaneous excitatory postsynaptic currents |
| title | Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 |
| title_full | Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 |
| title_fullStr | Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 |
| title_full_unstemmed | Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 |
| title_short | Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1 |
| title_sort | chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine type 1 |
| topic | Spreading depolarization Pregabalin Familial hemiplegic migraine Spontaneous excitatory postsynaptic currents |
| url | https://doi.org/10.1186/s13041-023-01062-6 |
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