A Role for Dopamine-Mediated Learning in the Pathophysiology and Treatment of Parkinson’s Disease

Abstract

Dopamine contributes to corticostriatal plasticity and motor learning. Dopamine denervation profoundly alters motor performance, as in Parkinson’s disease; however, the extent to which these symptoms reflect impaired motor learning is unknown. Here we demonstrate a D2 receptor blockade induced aberrant learning that impedes future motor performance when dopamine signaling is restored, an effect diminished by co-administration of adenosine antagonists during blockade. We hypothesize that an inappropriate corticostriatal potentiation in striatopallidal cells of the indirect pathway underlies aberrant learning. Here, we demonstrate synaptic potentiation in striatopallidal neurons induced by D2 blockade and diminished by application of an adenosine antagonist, consistent with behaviaoral observations. A neurocomputational model of the basal ganglia recapitulates the behavioral pattern and further links aberrant learning to plasticity in the indirect pathway. Thus, D2-mediated aberrant learning may contribute to motor deficits in PD and suggest new avenues for the development of therapeutics.

Dissociable effects of dopamine on learning and performance within sensorimotor striatum

“…It is not yet clear why selective D2 receptor blockade did not cause experience-dependent changes (“NOGO” learning), as observed for rotarod performance [27]. The presence of D2 receptors at multiple pre- and post-synaptic locations in striatum [24], together with the limited set of doses used in these experiments, make interpretation of the raclopride results more challenging.…”

“…It may arise through dopamine-modulated synaptic plasticity that normally supports reinforcement learning [21–25]. With decreased striatal dopamine signaling, normal learning of motor skills is impaired [26], aberrant learning can occur [27], and established performance of various operant tasks may be initially preserved but decline with practice (“experience-dependent” effects; [28,29]). BG output is important for the acquisition of motor sequences [30], but may not be required to perform previously learned sequences [31,32].…”

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

“…At corticostriatal synapses, DA regulates synaptic transmission (Calabresi et al, 1997a; Kreitzer and Malenka, 2005; Pawlak and Kerr, 2008; Reynolds and Wickens, 2002; Wang et al, 2006). Loss of DA signaling at these synapses results in aberrant synaptic transmission that likely contributes to functional changes in the basal ganglia circuitry underlying motor dysfunctions in many neurodegenerative disorders, including PD (Beeler et al, 2012; Calabresi et al, 2007; Kreitzer and Malenka, 2007; Shen et al, 2008). …”

Cognitive states influence dopamine-driven aberrant learning in Parkinson's disease

“…Phasic dopamine bursts in the cortico–striatal D1 receptor-mediated direct pathway underlie the ability to learn from and seek reward, whereas dopamine dips in the D2 receptor-mediated indirect pathway underlie the ability to learn from and avoid punishment (Kravitz et al, 2010; Kravitz, Tye, & Kreitzer, 2012; Porter-stransky, Seiler, Day, & Aragona, 2013; Tai, Lee, Benavidez, Bonci, & Wilbrecht, 2012). Reduced tonic dopamine in Parkinsonism causes a lower dynamic range of phasic signaling and a loss of synaptic plasticity in the direct pathway (Frank, 2005; Frank, Seeberger, & O’Reilly R, 2004), as well as opposite effects of more effective phasic signaling and enhanced long term potentiation in the indirect pathway (Beeler et al, 2012; Wiecki & Frank, 2010). The outcome of these systemic alterations include impaired reward-related learning and motivation for action selection (diminished D1 effects) (Voon et al, 2010) but also paradoxically boosted learning of active inhibition (enhanced D2 effects) (Kravitz et al, 2012).…”