Degeneration of substantia nigra (SN) dopaminergic (DA) neurons is specifically linked to the debilitating symptoms of akinesia, bradykinesia, and rigidity in Parkinson's disease (PD)1-3. Studies of familial PD, post- mortem tissue from PD patients, and environmental toxins argue that mitochondrial dysfunction is key to pathogenesis4-10. Indeed, SN DA neurons manifest basal mitochondrial oxidant stress that should predispose them to dysfunction with age2,11,12. However, the relative contribution of cell-autonomous versus synaptically driven mitochondrial oxidant stress to the progressive degeneration of SN DA neurons in PD is poorly understood. Dysfunction and degeneration of SN DA neurons long precede the expression of motor symptoms in PD13-15. At the point of diagnosis, 50-70% of striatal DA axons and 30-40% of SN DA neurons no longer express tyrosine hydroxylase or have been lost, arguing that the disease has been underway for some time but there has been compensation13,16,17. Data from toxin models of PD suggest that the basal ganglia may compensate for the loss of DA transmission through increased synaptic excitation of remaining DA neurons18-22 and adaptive plasticity23-29. However, as the disease progresses, increasingly aberrant correlated, phasic, burst activity3,30-36 and maladaptive plasticity23-29 in the basal ganglia may create an excitotoxic environment for SN DA neurons, accelerating their degeneration37-41. Although plausible, a rigorous test of this hypothesis has not been possible because of the dearth of experimental models that adequately mimic disease progression42,43. We will therefore investigate how circuit pathophysiology and plasticity influences the function and survival of SN DA neurons in the newly developed MitoCI-Park mouse model (Project 1), which exhibits progressive DA neuron degeneration and levodopa-sensitive motor dysfunction. The model, which is generated by conditional deletion of a key subunit of mitochondrial complex I (MitoCI), has construct validity because loss of SN MitoCI function is a hallmark of clinical PD4,9. Furthermore, degeneration mimics that seen in humans, as it starts with loss of striatal axons and then encompasses cell bodies in the SN13,16,17. In addition, we will assess the sufficiency of basal ganglia pathophysiology to induce degeneration using chemogenetic strategies in wild-type or DJ-1 knockout44 mice ? neither of which normally exhibit SN DA neuron degeneration. These studies will utilize a combination of in vivo and ex vivo electrophysiological, optogenetic, chemogenetic, 2-photon imaging, electrochemical, immunohistochemical, and behavioral approaches. Better understanding of the complex interdependence of pathogenesis, plasticity, and circuit and motor dysfunction could inform novel therapeutic strategies that slow or prevent degeneration of SN DA neurons and ameliorate motor symptoms in PD.
| Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698 |
| Guzman, Jaime N; Ilijic, Ema; Yang, Ben et al. (2018) Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 128:2266-2280 |
| Higgs, Matthew H; Wilson, Charles J (2017) Measurement of phase resetting curves using optogenetic barrage stimuli. J Neurosci Methods 289:23-30 |
| Surmeier, D James; Obeso, José A; Halliday, Glenda M (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101-113 |
| Chu, Hong-Yuan; McIver, Eileen L; Kovaleski, Ryan F et al. (2017) Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron 95:1306-1318.e5 |
| Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926 |
| Surmeier, D James; Halliday, Glenda M; Simuni, Tanya (2017) Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Exp Neurol 298:202-209 |
| Galtieri, Daniel J; Estep, Chad M; Wokosin, David L et al. (2017) Pedunculopontine glutamatergic neurons control spike patterning in substantia nigra dopaminergic neurons. Elife 6: |
| Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2017) Calcium and Parkinson's disease. Biochem Biophys Res Commun 483:1013-1019 |
| Burbulla, Lena F; Song, Pingping; Mazzulli, Joseph R et al. (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255-1261 |
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