Maladaptive striatal plasticity and abnormal reward‐learning in cervical dystonia

Abstract

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

“…Impaired generation of LTP at iMSN cortico-striatal synapses following a risky "loss" is in the DYT1 patients is also analogous to the loss of iMSN LTP and increased LTD in a model of impaired reversal learning seen in patients with cervical dystonia [21]. These results support a common mechanism of deficient LTP and excess LTD at iMSN cortico-striatal synapse's causing abnormal reinforcement learning that is independent of the specifics of the task or dystonia phenotype.…”

“…The behavioural data was fitted to the cortico-striatal plasticity (CSP) model described in detail in Gilbertson et. al.…”

“…al. (2019) [21]. This combines a traditional temporal difference (TD) model of reinforcement learning with biologically plausible cortico-striatal synaptic weight changes based on in vitro data [5].…”

“…We wanted to address this conflict between the reported plasticity abnormalities demonstrated in rodent models and the risk taking behaviour observed in patients using a model of cortico-striatal plasticity [21]. In these simulations the model reproduced decision making in the task whilst being forced to learn under the three proposed conditions of abnormal striatal plasticity.…”

Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders

“…Although variants in Prkcg are specifically associated with the dystonic disorder spinocerebellar ataxia type 14 [41][42][43], identification of Prkcg in our proteomic analysis has broader implications for dystonia in light of the role of Prkcg in the regulation of synaptic plasticity. Abnormal plasticity is observed in many different forms of dystonia in humans and in several mouse models of dystonia [44][45][46][47][48][49][50], suggesting that Prkcg may be a pathophysiological node. Prrt2 is a presynaptic membrane protein that interacts with SNAP-25 to mediate calcium-dependent vesicular exocytosis, particularly glutamate release [51].…”