Transient Calcium and Dopamine Increase PKA Activity and DARPP-32 Phosphorylation

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Abstract
Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs. Reinforcement learning, based on the association of a stimulus-triggered movement with a reward, involves changes in connection strength between neurons. Memory storage occurs in the striatum, the input stage of the basal ganglia, when a stimulus or movement signal originating from the cortex and a reward signal originating from the midbrain reach the target striatal cells together. Repetitive pairing of these two signals strengthens the connection between cortical and striatal cells. The strengthening of the connections is caused by activation of biochemical signalling pathways inside the striatal cells. These intracellular signalling pathways are explored in a quantitative computational model describing the biochemical pathways important for reinforcement learning. Lindskog et al.'s study shows that when brief reward and stimuli signals are paired, a stronger response in the intracellular signalling occurs compared with the situation when each signal is given alone. This result illustrates mechanisms whereby paired stimuli, but not unpaired stimuli, can cause learning. Furthermore, the model predicts that the biochemical responses are different after brief stimulation as compared with prolonged stimulation. This result highlights the difficulties in predicting the nonlinear interactions within signalling cascades based on prolonged stimulations, which often are used in biochemical experiments.