The Morris K. Udall Center of Excellence for Parkinson's Disease Research at Northwestern University

Director: D. James Surmeier, PhD

Title: Rhythmicity and Synchrony in the Basal Ganglia

Central Theme and Center Structure

The Northwestern University Udall Center is focused on two major lines of study with strong translational potential. The first line of study focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the external segment of the globus pallidus (GP) and the subthalamic nucleus (STN). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified molecular adaptations in the GP-STN network in PD models that could be responsible for this pathophysiology. Our research teams are pursuing this discovery and will attempt to translate it into a gene therapy appropriate for late stage PD patients. The second line of study in our center builds upon recent insights gained into the factors underlying vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that are lost in PD. These studies suggest that the reliance upon voltage calcium channels to drive autonomous pacemaking renders SNc neurons vulnerable to mitochondrial insults. These studies also suggest this reliance can be reversed with a drug that is approved for human use. Studies currently underway examine the cellular and molecular basis for this linkage and pursue questions that should be answered prior to a clinical neuroprotection trial.

The Udall Center brings together five principal investigators (PIs) with complementary expertise from four research institutions (Mark D. Bevan, Ph.D. at Northwestern University, Charles J. Wilson, Ph.D. at the University of Texas San Antonio, Hitoshi Kita, Ph.D. at the University of Tennessee, and Pavel Osten, M.D., Ph.D. at Cold Spring Harbor Laboratory). In addition to research teams, the Center has an Administrative Core to coordinate activities of the projects and a Molecular Core to serve the genetic profiling and gene therapy aims of the projects.

Recent Significant Advances

The discovery that Ca2+ entry during autonomous pacemaking in vulnerable dopaminergic neurons leads to elevated mitochondrial oxidative stress and oscillations in the inner membrane potential. This oxidative stress is exacerbated by genetic deletion of DJ-1. Antagonism of L-type Ca2+ with an FDA approved drug dramatically reduces oxidative stress without compromising cellular function. This work is now in press at Nature.

• The discovery that dopamine depletion induces a down-regulation of HCN channels in globus pallidus neurons, leading to a loss of autonomous activity. In the last year, we have shown that viral delivery of an HCN expression construct restores pacemaking in globus pallidus neurons but does not ameliorate the motor symptoms induced by dopamine depletion. This suggests that there are additional factors contributing to the pathophysiology in PD. This work has been accepted pending minor revision at Nature Neuroscience.
• The discovery that the intrinsic oscillatory capacity of dendrites in SNc dopaminergic neurons contributes to the ability to generate bursts of action potentials in response to glutamatergic inputs. The contribution of L-type channels to these bursts appears to be modest. These studies were published in two papers in the Journal of Neuroscience (Blythe et al., 2009; Deister et al., 2009).
• The discovery that HCN channels make a major contribution to synaptic integration in both globus pallidus and subthalamic neurons. This finding, in conjunction with the down-regulation of HCN expression in both regions following dopamine depletion, suggests that a distributed channelopathy could be a contributing factor in the pathophysiology of late stage PD.
• The discovery that locus ceruleus (LC) neurons, which are very vulnerable in PD, have a similar physiological phenotype to that of SNc dopaminergic neurons. We have found that these neurons are slow pacemakers that flux Ca2+ through L-type channels. This influx leads to mitochondrial membrane potential fluctuations, indicative of oxidant stress; however, these oscillations are less pronounced than those in SNc dopaminergic neurons. We have also found that cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) – another vulnerable cell group – share some of the physiological features of SNc and LC neurons. These neurons are slow, Ca2+-dependent pacemakers. However, unlike SNc and LC neurons, there are not oscillations in cytosolic Ca2+ concentration during pacemaking. These results suggest that there are common phenotypic determinants of neuronal vulnerability in PD that could be amenable to treatment with L-type channel antagonists.

Available Resources

In the next year, we anticipate being able to distribute transgenic mice expressing the redox sensitive probe roGFP under control of a tyrosine hydroxylase promoter with a mitochondrial matrix targeting sequence.

Plans for the Coming Year

We will continue our study of mitochondrial function in vulnerable dopaminergic neurons with the goal of determining the interaction between genes associated with familial forms of PD and calcium mediated stress. Having completed our initial studies of DJ-1 null mice, we will focus on PINK1 nulls and LRRK2 mutant mice harboring the G2019S mutation. These studies will be done in collaboration with the Hopkins Udall Center.

• We continue our characterization of LC and DMV neurons. We have developed a line of transgenic mice that express mito-roGFP under control of the choline acetyltransferase promoter, giving us selective expression of this probe in cholinergic neurons.
• Our drug screening effort has identified a selective, small molecule antagonist of Cav1.3 Ca2+ channels implicated in creating mitochondrial oxidant stress in SNc dopaminergic neurons. In the next year, we will attempt to optimize the potency and selectivity of this antagonist using medicinal chemistry and then begin pre-clinical testing in animal models of PD. In parallel, we will complete our screening effort in an attempt to identify other chemical scaffolds.
• We will continue our characterization of functional adaptations in the GP-STN circuitry in late stage PD models. Our work is currently focusing on alterations in synaptic connectivity between the two nuclei subsequent to HCN down-regulation and intrinsic mechanisms governing repetitive activity, like that seen in late stage PD.
• We will expand our study of determinants of mitochondrial oxidant stress in SNc dopaminergic neurons to include ionotropic glutamate receptors. Recent work suggests that in the later stages of the disease, extracellular glutamate levels in the SNc rise, perhaps as a consequences of elevated activity in the STN or PPN. Our preliminary results suggest that Ca2+ influx through NMDA receptors makes a significant contribution to oxidant stress under basal, nominally unstimulated conditions.

Select Recent Publications

Barraza, D. , Kita, H. and Wilson, C.J. (2009) Slow spike frequency adaptation in neurons of the rat subthalamic nucleus. J. Neurophysiol. 102:3689-3697.
Blythe SN, Wokosin D, Atherton JF, Bevan MD (2009) Cellular mechanisms underlying burst firing in substantia nigra dopamine neurons. J Neurosci 29: 15531-41.
Chan CS, Gertler TS, Surmeier DJ (2009) Calcium homeostasis, selective vulnerability and Parkinson's disease. Trends Neurosci 32:249-256.
Deister, C.A., Teagarden, M.A., Wilson, C.J. and Paladini, C.A. (2009) An intrinsic neuronal oscillator underlies dopaminergic neuron bursting. J. Neurosci. 29:15888-15897.
Dodla, R. and Wilson, C.J. (2010) A phase function to quantify serial dependence between discrete samples. Biophys. J. 98:L5-7.
Dodla, R. and Wilson, C.J. (2010) Quantification of clustering in joint interspike interval scattergrams of spike trains. Biophys. J. 98:2535-2543.
Dodla, R. and Wilson, C.J. (2010) Coherence resonance due to transient thresholds in excitable systems. Phys. Rev. E 82:021105.
Farries M.A., Kita, H. and Wilson, C.J. (2010) Dynamic spike threshold and zero membrane slope conductance shape the response of subthalamic neurons to cortical input. J. Neurosci. In press.
Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ (2009) Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 29:11011-11019.
Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature in press.
Lewis AS, Schwartz E, Chan CS, Noam Y, Shin M, Wadman WJ, Surmeier DJ, Baram TZ, Macdonald RL, Chetkovich DM (2009) Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. J Neurosci 29:6250-6265.
Schuster S, Doudnikoff E, Rylander D, Berthet A, Aubert I, Ittrich C, Bloch B, Cenci MA, Surmeier DJ, Hengerer B, Bezard E (2009) Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia. Biol Psychiatry 65:518-526.
Simuni T, Borushko E, Avram MJ, Miskevics S, Martel A, Zadikoff C, Videnovic A, Weaver FM, Williams K, Surmeier DJ (2010) Tolerability of isradipine in early Parkinson's disease: A pilot dose escalation study. Mov Disord.
Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA (2010) What causes the death of dopaminergic neurons in Parkinson's disease? Prog Brain Res 183:59-77.
Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA (2010) The origins of oxidant stress in Parkinson's disease and therapeutic strategies. Antioxid Redox Signal.
Surmeier DJ, Guzman JN, Sanchez-Padilla J (2010) Calcium, cellular aging, and selective neuronal vulnerability in Parkinson's disease. Cell Calcium 47:175-182.

Public Health Statement

Our Udall Center has two primary goals. The first goal is to gain a better understanding of the causes of PD. Our approach to this difficult problem has been to ask what is different about vulnerable dopaminergic neurons. This led us to the discovery that the engagement of a peculiar type of calcium channel in autonomous pacemaking increased the sensitivity of dopaminergic neurons to mitochondrial toxins used to create models of PD. Subsequently, we have shown that calcium entry through this channel increases mitochondrial oxidative stress and exacerbates the deleterious consequences of at least one genetic mutation associated with familial forms of the disease. The truly exciting thing about this discovery is that this channel is sensitive to an FDA approved class of drugs with an outstanding safety record. Clinical trials are underway in early stage PD patients to determine whether antagonizing this channel slows the progression of the disease. This insight has also spawned a drug discovery effort aimed at identifying new more potent and selective antagonists of this channel. This work has already yielded novel drugs that we are testing.

The second goal is to understand what happens to the motor circuitry of the brain when dopaminergic neurons are lost to the disease. If we can figure out how the network activity is changed, perhaps we can correct it. Although the problem is complex, this effort has already yielded a major insight into how the aberrant activity thought to be responsible for the inability to move arises. It appears that in an attempt to compensate for the loss of dopamine, neurons in the globus pallidus down-regulate a key ion channel that triggers a host of negative consequences. That is, in attempting to make things better, the neurons make things much worse. Although we have found that re-introduction of this gene in and of itself does not restore motor function in models of the disease, it is possible that this pathology is distributed. We are currently pursuing this hypothesis. This work holds the promise of a powerful new therapy for late stage PD patients.