Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses
Por:
Thomas, Rachel, Hernandez, Adan, Benavides, David R., Li, Wei, Tan, Chunfeng, Umfress, Alan, Plattner, Florian, Chakraborti, Ayanabha, Pozzo-Miller, Lucas, Taylor, Susan S., Bibb, James A.
Publicada:
1 ago 2021
Resumen:
Cortical glutamate and midbrain dopamine neurotransmission converge to
mediate striatum-dependent behaviors, while maladaptations in striatal
circuitry contribute to mental dis-orders. 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, RII
beta. Using a combination of biochemical, pharmacological,
neurophysiological, and behavioral approaches, we find that
glutamate-dependent reduction in cyclin-dependent kinase 5
(Cdk5)-dependent RII beta phosphorylation alters the PKA holoenzyme
autoinhibitory state to increase PKA signaling in response to dopamine.
Furthermore, we show that disruption of RII beta phosphorylation by Cdk5
enhances cortico-ventral striatal synaptic plasticity. In addition, we
demonstrate that acute and chronic stress in rats inversely modulate RII
beta phosphorylation and ventral striatal infusion of a small
interfering peptide that selectively targets RII beta 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.
Filiaciones:
Thomas, Rachel:
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Hernandez, Adan:
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico
Benavides, David R.:
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, United States
Li, Wei:
Department of Neurobiology, Civitan International Research Center, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
Tan, Chunfeng:
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States
Umfress, Alan:
Department of Surgery, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
Plattner, Florian:
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Chakraborti, Ayanabha:
Department of Surgery, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
Pozzo-Miller, Lucas:
Department of Neurobiology, Civitan International Research Center, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
Taylor, Susan S.:
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, United States
Bibb, James A.:
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Department of Neurobiology, Civitan International Research Center, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
Department of Surgery, The University of Alabama Birmingham Medical Center, Birmingham, Alabama, United States
gold, Green Published, Green Submitted, Gold, Green
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