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

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. In our brain, learning and memory are strongly modulated by dopamine (DA) signals. Even a short absence of DA (0.5-2 s), called "DA dip," triggers long-term memory formation, the underlying processes of which are hitherto largely unknown. Here, we examined how the DA dips are processed through a biochemical signaling network to generate long-term memory. Computer simulation and theoretical analyses showed that the DA-dip signal is processed only if the levels of two key molecules, DA D2 receptor (D2R) and regulators of G protein signaling (RGS), are both delicately balanced. This balance seems to be achieved in the healthy brain, whereas imbalance between D2R and RGS levels appear in patients with schizophrenia and DYT1 dystonia, both of which may manifest abnormal long-term memory. The D2R-RGS imbalances hamper DA-dip detectability, and thus disturb long-term memory formation, which may result in the symptoms of schizophrenia and dystonia. The balance between D2R and RGS appear to be finely regulated in the healthy brain to underpin normal learning and memory.