AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula
Abstract The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain’s processing of rewarding/...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-06041-8 |
| _version_ | 1797247095154933760 |
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| author | Sarah C. Simmons William J. Flerlage Ludovic D. Langlois Ryan D. Shepard Christopher Bouslog Emily H. Thomas Kaitlyn M. Gouty Jennifer L. Sanderson Shawn Gouty Brian M. Cox Mark L. Dell’Acqua Fereshteh S. Nugent |
| author_facet | Sarah C. Simmons William J. Flerlage Ludovic D. Langlois Ryan D. Shepard Christopher Bouslog Emily H. Thomas Kaitlyn M. Gouty Jennifer L. Sanderson Shawn Gouty Brian M. Cox Mark L. Dell’Acqua Fereshteh S. Nugent |
| author_sort | Sarah C. Simmons |
| collection | DOAJ |
| description | Abstract The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain’s processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb. |
| first_indexed | 2024-04-24T19:53:14Z |
| format | Article |
| id | doaj.art-d0756070792248e3952cc58c533d07ad |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-04-24T19:53:14Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-d0756070792248e3952cc58c533d07ad2024-03-24T12:29:21ZengNature PortfolioCommunications Biology2399-36422024-03-017111410.1038/s42003-024-06041-8AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenulaSarah C. Simmons0William J. Flerlage1Ludovic D. Langlois2Ryan D. Shepard3Christopher Bouslog4Emily H. Thomas5Kaitlyn M. Gouty6Jennifer L. Sanderson7Shawn Gouty8Brian M. Cox9Mark L. Dell’Acqua10Fereshteh S. Nugent11Uniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsDepartment of Pharmacology, University of Colorado School of Medicine, Anschutz Medical CampusUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsDepartment of Pharmacology, University of Colorado School of Medicine, Anschutz Medical CampusUniformed Services University of the Health Sciences, Department of Pharmacology and Molecular TherapeuticsAbstract The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain’s processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.https://doi.org/10.1038/s42003-024-06041-8 |
| spellingShingle | Sarah C. Simmons William J. Flerlage Ludovic D. Langlois Ryan D. Shepard Christopher Bouslog Emily H. Thomas Kaitlyn M. Gouty Jennifer L. Sanderson Shawn Gouty Brian M. Cox Mark L. Dell’Acqua Fereshteh S. Nugent AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula Communications Biology |
| title | AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula |
| title_full | AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula |
| title_fullStr | AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula |
| title_full_unstemmed | AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula |
| title_short | AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula |
| title_sort | akap150 anchored pka regulates synaptic transmission and plasticity neuronal excitability and crf neuromodulation in the mouse lateral habenula |
| url | https://doi.org/10.1038/s42003-024-06041-8 |
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