Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus
Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, inc...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/24/13604 |
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| author | Paulina Kazmierska-Grebowska Marcin Siwiec Joanna Ewa Sowa Bartosz Caban Tomasz Kowalczyk Renata Bocian M. Bruce MacIver |
| author_facet | Paulina Kazmierska-Grebowska Marcin Siwiec Joanna Ewa Sowa Bartosz Caban Tomasz Kowalczyk Renata Bocian M. Bruce MacIver |
| author_sort | Paulina Kazmierska-Grebowska |
| collection | DOAJ |
| description | Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABA<sub>A</sub>-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy. |
| first_indexed | 2024-03-10T03:54:21Z |
| format | Article |
| id | doaj.art-2275681e4f53416ba2b2f129e212dbe8 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:54:21Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2275681e4f53416ba2b2f129e212dbe82023-11-23T08:48:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241360410.3390/ijms222413604Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat HippocampusPaulina Kazmierska-Grebowska0Marcin Siwiec1Joanna Ewa Sowa2Bartosz Caban3Tomasz Kowalczyk4Renata Bocian5M. Bruce MacIver6Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Physiology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, PolandDepartment of Physiology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USATheta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABA<sub>A</sub>-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.https://www.mdpi.com/1422-0067/22/24/13604I<i>h</i> currentlamotrigineHCN channelstheta rhythmlocal field potentialsIPSCs |
| spellingShingle | Paulina Kazmierska-Grebowska Marcin Siwiec Joanna Ewa Sowa Bartosz Caban Tomasz Kowalczyk Renata Bocian M. Bruce MacIver Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus International Journal of Molecular Sciences I<i>h</i> current lamotrigine HCN channels theta rhythm local field potentials IPSCs |
| title | Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus |
| title_full | Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus |
| title_fullStr | Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus |
| title_full_unstemmed | Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus |
| title_short | Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus |
| title_sort | lamotrigine attenuates neuronal excitability depresses gaba synaptic inhibition and modulates theta rhythms in rat hippocampus |
| topic | I<i>h</i> current lamotrigine HCN channels theta rhythm local field potentials IPSCs |
| url | https://www.mdpi.com/1422-0067/22/24/13604 |
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