Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex

Abstract

In Parkinson's disease (PD), dopamine depletion causes dramatic changes in the brain resulting in debilitating cognitive and motor deficits. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time point of PD progression. Models of PD where dopamine tone in the brain are chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this paper, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo, time-lapse imaging and motor-skill behavior assays. In combination with previous studies, a role of the motor cortex in skill-learning, and the impairment of this ability with the loss of dopamine, is becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in the motor-skill learning and cognitive impairments of PD, with the possibility of targeting the motor cortex for future PD therapeutics.Parkinson disease (PD) is a chronic, disabling neurological disease that affected over 4 million people worldwide over the age of 50 in 2005, and is expected double by 2030 1,2,3 . In addition to motor deficits, cognitive deficits, including the impairment of motor skilllearning, are frequent comorbidities in PD: nearly 80% of PD patients eventually develop 4,5 . Progressive degeneration of nigrostriatal dopaminergic neurons is the pathophysiological hallmark of PD, resulting in dramatically reduced dopamine tone in the brains of PD patients 6,7,8 . HHS Public AccessThe most well documented disruption of neural circuitry in PD occurs in the basal ganglia, a composite of several brain structures densely innervated by the dopaminergic system 9 . It is widely accepted that dysfunction of basal ganglia circuitry via the basal ganglia-thalamocortical pathway is responsible for the development of the motor movement disorders observed in PD: the loss of dopaminergic neurons results in excessive activation of the basal ganglia output nuclei and subsequent inhibition of thalamocortical and brainstem motor systems. Therefore, the loss of nigrostriatal dopamine tone is what is thought to ultimately result in the motor dysfunctions observed in PD 10,11 .The neuropathology of PD has been documented principally and extensively through postmortem examination, providing a detailed snapshot of a PD brain at a single time point 12,13 . While much has been discovered regarding the cause of movement disorders in PD, there is little information about the cognitive and skill-learning deficits also present in PD patients. Recent studies have co...

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