In the last grant period, our studies focused on intrinsic determinants of neuronal vulnerability in Parkinson's disease (PD). In the renewal application, we propose to pursue extrinsic, network-based determinants of neuronal vulnerability in PD, focusing on the innervation the innervation of the SNc by the pedunculopontine nucleus (PPN). The PPN provides the SNc with a rich glutamatergic and cholinergic innervation. Both glutamatergic and cholinergic signaling have been implicated in PD pathogenesis, but until recently, rigorous characterization of the role of these two PPN projection systems in regulating the activity and stress levels of SNc dopaminergic neurons has not been possible. This situation has now fundamentally changed with the advent of optogenetic and pharmacogenomic approaches. Using these new tools, we propose to pursue four specific aims with translational potential.
Specific Aim 1 : Determine whether PPN glutamatergic synapses on SNc dopaminergic neurons increase their oxidant stress. Our working hypothesis is that PPN terminal release of glutamate activates GluN2D-containing NMDA receptors (NMDARs) in proximal dendrites of SNc dopaminergic neurons, leading to an elevation in Ca2+ concentration and mitochondrial oxidant stress.
Specific Aim 2 : Determine whether PPN cholinergic synapses on SNc dopaminergic neurons decrease their oxidant stress. Our working hypothesis is that PPN terminal acetylcholine release activates ?4?2- and ?6?2-containing postsynaptic nicotinic receptors (nAChRs) and that repetitive activation of these terminals, leads to suppression in Cav1.3 channel currents and diminished mitochondrial oxidant stress.
Specific Aim 3 : Determine whether chronic nicotine administration decreases mitochondrial oxidant stress in SNc DA neurons. Our working hypothesis is that chronic nicotine administration suppresses intracellular Ca2+ oscillations driven by Cav1.3 channels during pacemaking and dis-facilitates glutamate release from PPN glutamatergic terminals, leading to a significant drop in mitochondrial oxidant stress and enhanced function.
Specific Aim 4 : Determine whether pharmacogenomic suppression of PPN glutamatergic neurons enhances the survival and function of SNc dopaminergic neurons in a mouse model of PD. Our working hypothesis is that dopamine depletion drives pathophysiological activity in PPN glutamatergic neurons, which increases oxidant stress levels in SNc DA neurons and accelerates their loss in PD models. The achievement of these aims could lead to the development of novel drugs targeting specific sub-classes of NMDARs and nAChRs that could be used in combination with Cav1.3 Ca2+ channel antagonists to slow or stop the progression of PD.

Public Health Relevance

The proposed studies are aimed at determining the factors responsible for the death of dopaminergic neurons in Parkinson's disease. Several hypotheses will be tested that could lead to new neuroprotective strategies, including one that is based upon the long-standing observation that smoking tobacco diminishes the risk of developing Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1)
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Northwestern University at Chicago
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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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