AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Autor: Simmons SC; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Flerlage WJ; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Langlois LD; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Shepard RD; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Bouslog C; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Thomas EH; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Gouty KM; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Sanderson JL; Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA., Gouty S; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Cox BM; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA., Dell'Acqua ML; Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA., Nugent FS; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, Maryland 20814, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 07. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1101/2023.12.06.570160
Abstrakt: Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABA A receptor (GABA A R)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABA A R synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.
Competing Interests: Competing interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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