Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to corticostriatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4± 22.0% and LTD protocol: 52.1± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

The D 1 dopamine receptor, G protein ␥ 7 subunit, and adenylylcyclase are selectively expressed in the striatum, suggesting their potential interaction in a common signaling pathway. To evaluate this possibility, a ribozyme strategy was used to suppress the expression of the G protein . Studies suggest that imbalances between these two opposing classes lead to deficiencies in movement and cognitive performance (2, 3). In particular, alterations in the D 1 -like dopamine receptors are implicated in a variety of neurologic and psychiatric disorders, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. Thus, achieving a better understanding of the D 1 -like dopamine receptors and the signaling pathways they activate may suggest more selective therapeutic targets in these diseases.The D 1 and D 5 dopamine receptors stimulate adenylylcyclase activity through their coupling to heterotrimeric G proteins (1, 4 -6). Because the function of these heterotrimeric G proteins was originally ascribed to the ␣ subunit, most research has focused on determining its identity. Of the several ␣ subunits identified to date, reconstitution studies have shown that coupling of D 1 dopamine receptors to adenylylcyclase can be mediated only by the ␣ s and ␣ olf subunits of the G s subclass (4, 5, 7-9). Although sharing 88% amino acid homology, the ␣s and ␣ olf subunits show very divergent expression patterns, ranging from the ubiquitous expression of the ␣ s subunit to the olfactory and neuron-specific expression of the ␣ olf subunit (10). Immunoprecipitation studies (11) have confirmed the interaction between the ␣ s subunit and the D 1 dopamine receptors in cells, whereas in situ hybridization (12, 13) and gene targeting (14) studies have suggested a possible interaction between the ␣ olf subunit and the D 1 dopamine receptor in striatum.By contrast, little effort has focused on determining the identity of the ␤␥ subunits of the G protein despite mounting evidence for their importance in receptor recognition (15,16). Of particular interest, reconstitution studies (17-21) and reverse genetic approaches (22,23) have shown that the nature of the ␥ subunit is an important determinant of its interaction with receptor. Consistent with such a role, 12 ␥ subunit genes have been identified that show extensive structural diversity (24). Recently, we used a ribozyme approach to begin to elucidate their functions (23,25,26). This approach identified the ␥ 7 subunit as a specific component of the G protein that couples the ␤-adrenergic receptor, but not the prostaglandin E 1 receptor, to stimulation of adenylylcyclase in HEK 293 cells (23). Although expressed in a variety of tissues and cell types (27,28), the ␥ 7 subunit expression is most abundant in medium spiny neurons in striatum (13). This pattern of expression is shared by the D 1 dopamine receptor and adenylylcyclase (4, 12, 29 -31), raising the possibility that all of these components may be involved in the same signaling pathway. In the present study, we used the ribozyme ...

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Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by pathognomonic motor abnormalities that lead to significant disability and morbidity in advanced stages. PD is also associated with sleep abnormalities such as increased fragmentation, insomnia, and excessive daytime sleepiness. Little is known of the underlying mechanisms, in part due to the limited ability of existing mouse models to adequately replicate human PD patient sleep phenotypes. Here we characterize sleep-wake behavior in an innovative genetic mouse model of PD (MCI-Park) targeting a mitochondrial complex I gene (Ndufs2), which experiences progressive dopaminergic neuron loss and displays motor phenotypes resembling those seen in human PD. Methods Undisturbed sleep-wake behavior during 12 hr light: 12 hr dark cycles was evaluated in MCI-Park mice during prodromal stages (6-8 weeks of age) and later parkinsonian stages (14-18 weeks of age) as well as in age-matched wildtype littermate controls. Electroencephalographic (EEG) and electromyographic (EMG) recording electrodes were surgically implanted using sterile technique in male and female MCI-Park and wildtype mice. After one week of recovery and acclimation to recording chambers, EEG and EMG were recorded continuously and sleep phenotypes were analyzed. Results In prodromal stages, MCI-Park mice exhibited similar overall sleep state amounts compared to wildtype mice, however there were significantly more state shifts as well as longer bouts of wakefulness and shorter bouts of non-REM (NREM) sleep. As mice progressed to parkinsonian stages, these fragmentation measures worsened. In addition, parkinsonian MCI-Park mice experienced a significant increase in wakefulness, a significant reduction in NREM sleep amount, and alterations in REM sleep, with pronounced reductions in REM sleep amount and number of REM bouts. Power spectral analysis revealed consistent decreases in theta2 (also known as alpha) power across all sleep-wake states in MCI-Park mice. Conclusion These results indicate that mice harboring a genetic defect causing selective disruption of dopaminergic neurons exhibit progressive sleep abnormalities that resemble sleep disturbances in PD patients. This model thus offers an opportunity to evaluate mechanisms underlying and therapeutic strategies targeting altered sleep in PD patients. Support (if any) This work was supported by the Department of Defense award number W81XWH-21-0582 (F.W.T. and D.J.S.).