Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses

Rachel Thomas, Adan Hernandez, David R. Benavides, Wei Li, Chunfeng Tan, Alan Umfress, Florian Plattner, Ayanabha Chakraborti, Lucas Pozzo-Miller, Susan S. Taylor, James A. Bibb

Research output: Contribution to journalArticlepeer-review

Abstract

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIβ phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIβ phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

Original languageEnglish (US)
Article number102245
JournalJournal of Biological Chemistry
Volume298
Issue number8
DOIs
StatePublished - Aug 2022

Keywords

  • Cdk5
  • dopamine
  • glutamate
  • PKA
  • plasticity
  • RIIβ
  • stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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