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

Simmons, S. C.; Ferlage, W. J.; Langlois, L. D.; Shepard, R. D.; Bouslog, C.; Thomas, E. H.; Gouty, K. M.; SANDERSON, J. L.; Gouty, S.; Cox, B. M.; Dell'Acqua, M. L.; Nugent, F. S.

doi:10.1101/2023.12.06.570160

bioRxiv · 10.1101/2023.12.06.570160

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

Simmons, S. C.·Ferlage, W. J.·Langlois, L. D.·Shepard, R. D.·Bouslog, C.·Thomas, E. H.·Gouty, K. M.·SANDERSON, J. L.·Gouty, S.·Cox, B. M.·Dell'Acqua, M. L.·Nugent, F. S.

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Abstract

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 brains 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 {Delta}PKA 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, {Delta}PKA mutation potentiated GABAA receptor (GABAAR)-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 {Delta}PKA 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. {Delta}PKA 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 GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

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Simmons, S. C., Ferlage, W. J., Langlois, L. D., Shepard, R. D., Bouslog, C., Thomas, E. H., Gouty, K. M., SANDERSON, J. L., Gouty, S., Cox, B. M., Dell'Acqua, M. L., Nugent, F. S.. 2023-12-07. AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula. https://doi.org/10.1101/2023.12.06.570160

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