The critical balance between dopamine D2 receptor and RGS for the sensitive detection of a transient decay in dopamine signal

• Published in: PLoS computational biology 2021-09, Vol.17 (9), p.e1009364-e1009364
• Main Authors: Urakubo, Hidetoshi, Yagishita, Sho, Kasai, Haruo, Kubota, Yoshiyuki, Ishii, Shin
• Format: Article
• Language: English
• Subjects: Adenosine; Adenylate cyclase; Adenylyl Cyclases - physiology; Animals; Biology and Life Sciences; Brain research; Cellular signal transduction; Competition; Computational Biology; Computational neuroscience; Corpus Striatum - physiology; Development and progression; Dopamine; Dopamine - physiology; Dopamine D2 receptors; Dopamine receptors; Dystonia; Dystonia Musculorum Deformans - physiopathology; Enzymes; Exact solutions; GTP-Binding Proteins - physiology; Health aspects; Humans; Hydrolases; Intracellular signalling; Kinases; Learning - physiology; Long-term potentiation; Long-Term Potentiation - physiology; Medicine and Health Sciences; Mental disorders; Mental Disorders - physiopathology; Mental illness; Models, Neurological; Movement disorders; Movement Disorders - physiopathology; Neostriatum; Neurons - physiology; Physiological aspects; Proteins; Receptors; Receptors, Dopamine D2 - physiology; Reinforcement; Research and Analysis Methods; Reward; Risk factors; Schizophrenia; Schizophrenia - physiopathology; Signal Transduction - physiology; Signaling
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1009364

In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0.5-2 s) is transferred through intracellular signaling to the coincidence detector, adenylate cyclase (AC). In the present study, we built a computational model of D2 signaling to determine conditions for the DA-dip detection. The DA dip can be detected only if the basal DA signal sufficiently inhibits AC, and the DA-dip signal sufficiently disinhibits AC. We found that those two requirements were simultaneously satisfied only if two key molecules, D2R and regulators of G protein signaling (RGS) were balanced within a certain range; this balance has indeed been observed in experimental studies. We also found that high level of RGS was required for the detection of a 0.5-s short DA dip, and the analytical solutions for these requirements confirmed their universality. The imbalance between D2R and RGS is associated with schizophrenia and DYT1 dystonia, both of which are accompanied by abnormal striatal LTP. Our simulations suggest that D2 SPNs in patients with schizophrenia and DYT1 dystonia cannot detect short DA dips. We finally discussed that such psychiatric and movement disorders can be understood in terms of the imbalance between D2R and RGS.