Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice
In spinal muscular atrophy (SMA), mutations in or loss of the <i>Survival Motor Neuron 1</i> (<i>SMN1</i>) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7648 |
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| author | Rocio Tejero Mohammad Alsakkal Luisa Hennlein Ana M. Lopez-Cabello Sibylle Jablonka Lucia Tabares |
| author_facet | Rocio Tejero Mohammad Alsakkal Luisa Hennlein Ana M. Lopez-Cabello Sibylle Jablonka Lucia Tabares |
| author_sort | Rocio Tejero |
| collection | DOAJ |
| description | In spinal muscular atrophy (SMA), mutations in or loss of the <i>Survival Motor Neuron 1</i> (<i>SMN1</i>) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca<sup>2+</sup> transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands. |
| first_indexed | 2024-03-11T04:55:21Z |
| format | Article |
| id | doaj.art-a9ca653b21754c97bb1b0bb5a293e85e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:55:21Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a9ca653b21754c97bb1b0bb5a293e85e2023-11-17T19:43:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248764810.3390/ijms24087648Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA MiceRocio Tejero0Mohammad Alsakkal1Luisa Hennlein2Ana M. Lopez-Cabello3Sibylle Jablonka4Lucia Tabares5Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, SpainInstitute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, GermanyInstitute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, GermanyDepartment of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, SpainInstitute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, GermanyDepartment of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, SpainIn spinal muscular atrophy (SMA), mutations in or loss of the <i>Survival Motor Neuron 1</i> (<i>SMN1</i>) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca<sup>2+</sup> transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.https://www.mdpi.com/1422-0067/24/8/7648spinal muscular atrophymotor neuronssynaptic transmissionneuromuscular junctioncalcium channelsnifedipine |
| spellingShingle | Rocio Tejero Mohammad Alsakkal Luisa Hennlein Ana M. Lopez-Cabello Sibylle Jablonka Lucia Tabares Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice International Journal of Molecular Sciences spinal muscular atrophy motor neurons synaptic transmission neuromuscular junction calcium channels nifedipine |
| title | Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice |
| title_full | Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice |
| title_fullStr | Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice |
| title_full_unstemmed | Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice |
| title_short | Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice |
| title_sort | nifedipine ameliorates cellular differentiation defects of smn deficient motor neurons and enhances neuromuscular transmission in sma mice |
| topic | spinal muscular atrophy motor neurons synaptic transmission neuromuscular junction calcium channels nifedipine |
| url | https://www.mdpi.com/1422-0067/24/8/7648 |
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