AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula

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...

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Published in:	Communications biology Vol. 7; no. 1; p. 345
Main Authors:	Simmons, Sarah C., Flerlage, William J., Langlois, Ludovic D., Shepard, Ryan D., Bouslog, Christopher, Thomas, Emily H., Gouty, Kaitlyn M., Sanderson, Jennifer L., Gouty, Shawn, Cox, Brian M., Dell’Acqua, Mark L., Nugent, Fereshteh S.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 20-03-2024 Nature Publishing Group Nature Portfolio
Subjects:	14/1 14/63 631/378/340 631/378/87 64/110 9/74 A Kinase Anchor Proteins - genetics A Kinase Anchor Proteins - metabolism A kinase-anchoring protein Animals Biomedical and Life Sciences Corticotropin-releasing hormone Corticotropin-Releasing Hormone - metabolism Endocannabinoids Excitability Glutamatergic transmission Habenula Habenula - metabolism Kinases Life Sciences Long-term depression Luteinizing hormone Male Mice Mutation Neuromodulation Neuronal Plasticity - physiology Neurons - physiology Proteins Receptors, AMPA - genetics Receptors, AMPA - metabolism Receptors, GABA-A - metabolism Synaptic plasticity Synaptic strength Synaptic transmission Synaptic Transmission - physiology α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors γ-Aminobutyric acid A receptors
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Summary:	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 GABA A 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 GABA A receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb. A preclinical study in mice suggests important roles for a scaffold protein, A-kinase anchoring protein 150 (AKAP150) in regulation of synaptic function, glutamatergic plasticity and intrinsic excitability of lateral habenula (LHb) neurons.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2399-3642 2399-3642
DOI:	10.1038/s42003-024-06041-8