Striatal neurons get a kick out of dopamine

Abstract

Dopamine (DA) is critically involved in reinforcement learning, and malfunction in dopamine signalling is associated with numerous brain disorders, including attention deficit hyperactivity disorder, Parkinson's disease, drug abuse and schizophrenia. DA neurons are spontaneously active, but diverge from the baseline activity with brief bursts or pauses when animals are presented with cues that predict future reward (punishment or omission of expected reward counts as negative reward and causes a brief pause in DA cell firing). It is often assumed that phasic variations in striatal DA concentration are integrated by postsynaptic D1-like and D2-like receptors (Dreyer et al. 2016). These are linked to biochemical cascades that regulate the synaptic strength of cortical inputs to the basal ganglia that underlie incentive-based behaviour. Consequently compounds that amplify DA signalling are strongly addictive (Di Chiara et al. 2004). But are D1-and D2-regulated cascades fast enough for real-time processing of reward? Are phasic changes in DA levels sufficient to activate these cascades? What concentration of DA is required to activate or inhibit these cascades? Since the pathways in question involve complex G-protein-regulated biochemical cascades, the question of how temporal variations in DA levels affect postsynaptic neurons has been difficult to address experimentally.In this issue of The Journal of Physiology, Yapo et al. (2017) provide important new information on D1-and D2-regulated signals in striatal slices. Using UV-uncaged DA they examined activation of genetically encoded biosensors for cAMP and protein kinase A (PKA). Further, they constructed mathematical models of D1 and D2 receptor-regulated signalling to simulate conditions that resemble the expected natural reward signals. Thereby they showed that brief variations in DA signals are sufficient to elicit changes in second messenger signals and thereby possibly mediate longterm plasticity. Yapo et al. (2017) first showed that levels of cAMP in MSNs relate to phasic changes in dopamine: DA transients evoked a transient increase in cAMP levels in D1-positive MSNs while in D2-positive MSNs DA transients could inhibit cAMP evoked by an adenosine A2A receptor agonist. They then investigated intracellular signalling downstream of cAMP. Here they used AKAR3, a surrogate substrate of PKA that reports the equilibrium state of PKA and phosphatase (for example PP1) activity. Thus while in D1-MSNs cAMP accumulation also led to increased phosphorylation status, the corresponding link between cAMP and AKAR3 signals was much weaker in D2-MSNs. The dose-response relationship for DA activation and inhibition of MSNs revealed that D1-MSNs and D2-MSNs responded equally potently to transient DA stimulation, challenging the common notion that D2 receptors are more potent than D1 receptors.These data were next used to constrain mass-action models for D1-and D2-regulated signalling (Nair et al. 2015). The models included the canonical signalling cascades from DA receptors, ...