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Characterization of high gamma cortical oscillations during L-dopa-induced dyskinesias in an animal model of Parkinson's disease


Katherine Eyring Photo

Wellesley College (Massachusetts)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) and dopaminergic neurons in the basal ganglia. PD primarily affects the motor system, causing rigidity, slowness of movement, resting tremors, and lack of motor coordination. Early stage PD patients are often treated with DA receptor agonists, which directly stimulate DA D1 and D2 receptors within the basal ganglia to restore movement capabilities. Regrettably, as PD progresses DA agonists’ become less effective, prompting the use of Levodopa (L-dopa), the precursor to DA. L-dopa readily crosses the blood-brain barrier to restore DA levels throughout the basal ganglia and alleviate the motor symptoms of PD. However, prolonged L-dopa treatment often leads to the development of abnormal involuntary movements (AIMs), otherwise known as L-dopa-induced dyskinesia (LID) that are attributed to stimulation of DA receptors. Recently, the incidence of LID has been associated with robust, high frequency (70-110 Hz) oscillations in the motor cortex of an animal model of PD, and similar oscillations have been observed in human PD patients who were treated with L-dopa.

The present study sought to further characterize the relationship between high gamma oscillations in the motor cortex and the development of dyskinetic behavior. To do so, hemiparkinsonian rats were chronically implanted with electrode bundles targeting layers 5/6 of the motor cortex. Two weeks following DA lesion, animals were primed daily with L-dopa for 7 days. Local field potentials (LFPs), neuronal activity, and dyskinetic behavior were recorded periodically. Following-L-dopa priming, rats received L-dopa, the D1 agonist SKF81297, or the D2 agonist Quinpirole to induce dyskinesia. During peak dyskinesia, rats were treated with the serotonin (5-HT) 1A agonist 8-OH-DPAT, which is known to reduce dyskinesia. The effects of 8-OH-DPAT were reversed with the administration of the 5-HT1A antagonist WAY100635.

Findings strongly support a relationship between the expression and intensity of high gamma oscillations in the motor cortex and dyskinesia. Moreover, both the dyskinetic behavior and oscillatory activity are subject to a "priming effect" characterized by earlier onset and increased intensity. Interestingly, dyskinetic behavior was found to precede the emergence of the high gamma band, suggesting that the high gamma oscillations within the motor cortex may be correlative, rather than causative. In addition to L-dopa treatment, the D1 and D2 receptor agonists independently induced dyskinesia and the high gamma oscillations. Administration 8-OH-DPAT concurrently diminished high gamma cortical activity and the expression of dyskinesia; importantly, these effects were reversed with WAY100635. These results suggest that the high gamma activity and dyskinetic behavior are neither D1 nor D2 receptor specific and further implicates a correlative relationship between dyskinesia and cortical high gamma oscillations. Cortical spiking activity and  LFPs  were significantly phase-locked in the high gamma range (70-110 Hz) across many behaviors. Surprisingly, spike-LFP phase-locking decreased during dyskinesia, suggesting an inverse relationship between high gamma oscillations and spiking activity. This inverse relationship suggests synchronized input from other brain regions may contribute to high gamma oscillations more than spiking activity within cortical subcircuits. Further investigation into this high gamma phenomenon is paramount for understanding the mechanisms of LID and may ultimately lead to more effective treatment for PD patients.

Last updated November 26, 2013