Abstract
Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
Highlights
The basal ganglia integrates sensory and motivational signals to achieve goal-directed actions and cognition [1,2,3]
Recent brain imaging and neurophysiological studies suggest that the striatum, the start of the basal ganglia circuit, plays a major role in value-based decision making and behavioral disorders such as drug addiction
Further in silico experiments revealed that a positive feedback loop formed by proteins, the protein expressed in the striatum, served as the major switch for inducing long-term depression (LTD) and long-term potentiation (LTP)
Summary
The basal ganglia integrates sensory and motivational signals to achieve goal-directed actions and cognition [1,2,3]. The striatum, the input site of the basal ganglia, receives glutamatergic input from the cortex and dopaminergic input from the substantia nigra and the ventral tegmental area. While glutamatergic input without dopamine input results in long-term depression (LTD), coincident glutamatergic and dopaminergic inputs can cause long-term potentiation (LTP) [8,9]. This dopamine-dependent plasticity is a critical element for linking sensory and cognitive inputs from the cortex with reward-related signals from firing dopaminergic neurons to establish goal-directed behaviors [2]. Glutamatergic input in magnesiumfree solution, which results in massive calcium influx through
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