Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons

Abstract

Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via G olf -and G i/o -coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1Rϩ MSNs via ACh/M4R/G i/o and an ACh dip is required to gate a subset of D1R/G olf -dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2ϩ MSNs is under basal inhibition via D2R/G i/o and a DA dip leads to a PKA increase by disinhibiting A2aR/G olf , but D2ϩ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by G i/o and the importance of interactions between G i/o and G olf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.

The adenosine A2A receptor agonist, CGS 21680, attenuates a probabilistic reversal learning deficit and elevated grooming behavior in BTBR mice

“…Further, A 2A receptors in the striatum are almost exclusively expressed postsynaptically in striato-pallidal neurons of the indirect pathway [Moreno et al, 2017]. It has been shown that stimulation of adenosine A 2A receptors can counteract the inhibitory effects of dopamine D 2 receptors on striatal indirect pathway neurons [Nair, Gutierrez-Arenas, Eriksson, Vincent, & Hellgren Kotaleski, 2015]. Importantly, treatment with the A 2A receptor agonist, CGS 21680 alone has been shown to reduce drug-induced stereotypies in rodents and non-human primates [Andersen et al, 2002;Morelli, Pinna, Wardas, & Di Chiara, 1995] .…”

Striatal neurons get a kick out of dopamine

“…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, over G-proteins, adenylate cyclase, cAMP, PKA, to phosphorylation of T34 on DARPP-32.…”

“…Simulations of the native D2 system showed that PKA was indeed influenced by phasic DA. The analysis by Yapo et al (2017) shows that biosensors like AKAR3, which are subjected to multiple competing factors, should be interpreted carefully.One of the goals of the authors was to investigate if the intracellular signalling was sensitive to fast variations in dopamine levels observed from phasic cell firing, in particular whether a brief reduction of DA from the baseline, for example evoked by negative reward, can activate postsynaptic signals (Nair et al 2015;Dreyer et al 2016). This situation is not easily captured by UV-uncaging experiments.…”

“…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, over G-proteins, adenylate cyclase, cAMP, PKA, to phosphorylation of T34 on DARPP-32.…”

“…One of the goals of the authors was to investigate if the intracellular signalling was sensitive to fast variations in dopamine levels observed from phasic cell firing, in particular whether a brief reduction of DA from the baseline, for example evoked by negative reward, can activate postsynaptic signals (Nair et al 2015;Dreyer et al 2016). This situation is not easily captured by UV-uncaging experiments.…”