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 brings together five principal investigators (PIs) with complementary expertise from four research institutions (Northwestern University, University of Texas, University of Tennessee and 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.

Our 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 Parkinson's Disease (PD). Our group has identified adaptations in the GP-STN network in PD models that could be responsible for this pathophysiology. Our research teams are pursuing these discoveries and will attempt to translate it into new therapeutic approaches 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 engagement of voltage-gated calcium (Ca2+) channels during autonomous pacemaking helps to create a basal mitochondrial stress in SNc dopaminergic neurons, making them vulnerable to genetic mutations and environmental toxins. Other types of neuron that display vulnerability in PD, like neurons in the locus ceruleus and dorsal motor nucleus of the vagus appear to have a very similar physiological phenotype, replete with basal mitochondrial oxidant stress. Importantly, these studies also suggest this vulnerability can be diminished with a drug that is approved for human use, an inference supported by a number of recent epidemiological studies. A Phase II human clinical trial with the dihydropyridine isradipine has been completed and a Phase III proposal is being advanced. In addition, our Center initiated efforts to identify new and more powerful neuroprotective drugs. This effort has been successful and a new class of Ca2+ channel antagonists is in preclinical testing with the help of an NIH Blueprint for Neuroscience Research award from the NINDS.

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+ channels with an FDA approved drug (isradipine) dramatically reduces oxidative stress without compromising cellular function. This work was recently published in Nature (Guzman et al. 2010). We have followed up this work in two ways. First, we have developed a cell culture model of the mesencephalon in which dopaminergic neurons adopt a near mature phenotype. In these neurons, mitochondrial oxidant stress is elevated, particularly in dendrites. As in ex vivo brain slices, this stress is diminished by isradipine. Second, we have examined long-term treatment of mice with isradipine. These studies revealed that sustained isradipine treatment significantly diminished mitochondrial oxidant stress without compromising function, suggesting that there are beneficial consequences of sustained antagonism of L-type channels.
• One of the basic questions in PD is what factors underlie the pattern of pathology in the disease. Our work on SNc dopaminergic neurons suggests that a neuron’s physiological phenotype could be a major risk factor. If this is true, then other neurons lost or show signs of pathology (e.g., Lewy bodies) should share this phenotype. To test this hypothesis, we have studied two other at risk neuronal populations: locus ceruleus (LC) and dorsal motor nucleus of the vagus (DMV). We have found that both LC and DMV neurons have a physiological phenotype that strongly resembles that of SNc dopaminergic neurons, including a basal mitochondrial oxidant stress that is sensitive to antagonism of L-type Ca2+ channels. Our work on DMV neurons has just appeared in Nature Neuroscience (Goldberg et al.). Our work on LC is near submission.
• The neuroprotection afforded by systemic administration of the L-type channel antagonist isradipine is dose-dependent. In an intrastriatal 6-hydroxydopamine model of PD, half-maximal protection is afforded by serum concentrations of 4-5 ng/ml, which is very close to that achievable in humans within the FDA approved dose range. This work was recently published in Neurobiology of Disease (Ilijic et al. 2011).
• A Phase II clinical trial with the dihydrophyridine isradipine in early stage PD patients has been completed. This study was directed by Dr. Tanya Simuni and conducted by the Parkinson Study Group (PSG). The study found isradipine was well tolerated at 10 mg/day. Although not powered to determine the efficacy of the drug in slowing symptom progression, futility analysis of the outcome measures was encouraging, arguing that a larger scale, Phase III trial was warranted. This trial proposal will be submitted to the NINDS.
• Although isradipine has significant advantages as a therapeutic, it lacks specificity for Cav1.3 channels most tightly linked to oxidant stress in vulnerable neurons. We have launched a drug discovery effort to identify a more selective antagonist. This effort was successful and NIH has agreed to assist us in preclinical development of the drug through a Blueprint for Neuroscience Research award.
• We have made significant progress toward our specific aim to characterize the in vivo activity of pallidal and STN neurons in normal and dopamine (DA) depleted parkinsonian rats and monkeys. We found that DA depletion alters spontaneous activity and motor cortex stimulation-induced responses of entire basal ganglia nuclei and that the changes are in part attributable to increase in the activity of indirect pathway projection neurons in the striatum (Kita and Kita, 2011a and b; Tachibana et al., 2011). We also found that globus pallidus internal segment activity respond to cortical stimulation with an excessive inhibition in both parkinsonian and dystonia patients and animal models of parkinsonism and dystonia (Nambu et al., 2011; Kita and Kita, 2011a). On a related topic, our single axon tracing study revealed that a small population of layer 5b cortical neurons innervates the subthalamic nucleus. These cortical neurons have a small diameter parent axon and innervate multiple sites in the brain and spinal cord. The observations suggest that cortico-STN projection does not send an efferent copy of movement commands, as generally believed. Rather, it is likely that this projection is involved in associative control of movement (Kita and Kita, 2012).
• There is a consensus in the field that the pattern of spiking in the subthalamic nucleus and globus pallidus is an important factor in the pathophysiology of PD. As a consequence, the factors governing this patterning are important to understand. Because subthalamic neurons are spontaneously active, excitatory inputs act primarily to change the timing of action potentials, rather than to directly trigger them. We have completed a detailed analysis of phase-resetting by synaptic inputs to the STN neurons. This is the first comprehensive study of the dynamics of temporal integration of synaptic inputs in this structure.
• We also have found that the loss of dopamine leads, through an increase in the number of synaptic connections per GPe–STN axon terminal, to substantial strengthening of the GPe–STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.
• We have used our phase-resetting approach to develop a new theory of the therapeutic mechanism of action of deep brain stimulation that for the first time explains the well-known frequency dependence of DBS, and its requirement that the stimulus be periodic.
• Up until now, no conditional shRNA vector on an adeno-associated virus (AAV) shRNA backbone has been available to the biomedical community. To address this need, we have developed a conditional shRNA AAV vector. ShRNA for Cav1.3, Cav3.1, Cav3.3 have already been successfully packaged into AAV9, ready to be tested both in vitro as well as in vivo for both on-target as well as off-target effects. Most importantly, these molecular tools will help identify the cellular mechanism for the aberrant activity and plasticity that occur in the subthalamopallidal pathway in disease states. These AAVs will be distributed among different teams. In addition, we are in the process of the construction of few other shRNAs, including NR1. After an initial round of characterization, the plasmids generated will be made available to the community via Addgene.

Select Recent Publications

1. Cooper O et al. (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Science translational medicine 4(141):141ra90.
2. Fan, K. Y., Baufreton, J. Surmeier, D. J., Chan, C.S. and Bevan, M.D. Proliferation of External Globus Pallidus-Subthalamic Nucleus Synapses following Degeneration of Midbrain Dopamine Neurons, J. Neurosci. 32(40):13718-28
3. Farries, M.A. and Wilson, C.J. (2012) Phase response curves of subthalamic neurons measured with synaptic input and current injection.  J. Neurophysiol. 108(7):1822-37
4. Farries, M.A. and Wilson, C.J. (2012) Biophysical basis of the phase response curve of subthalamic neurons.  J. Neurophysiol. 108(7):1838-55
5. Fujita T, Fukai T, Kitano K (2012) Influences of membrane properties on phase response curve and synchronization stability in a model globus pallidus neuron. J. Comput Neurosci. 32(3):539-553
6. Glajch KE, Fleming SM, Surmeier DJ, Osten P (2012) Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease. Behav Brain Res. 230(2):309-316
7. Goldberg JA, Guzman JN, Estep CM, Ilijic E, Kondapalli J, Sanchez-Padilla J, Surmeier DJ (2012) Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. Nat Neurosci. 15(10):1414-21
8. Ilijic E, Guzman JN, Surmeier DJ (2011) The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis. 43(2):364-371
9. Jaeger D, Kita H (2011) Functional connectivity and integrative properties of globus pallidus neurons. Neuroscience 198:44-53
10. Kang, S., Cooper, G., Dunne, S. F., Dusel, B., Luan, C.-H., Surmeier, D.J. and Silverman, D.J. CaV1.3-selective L-type Ca2+  channel antagonists as potential new therapeutics for Parkinson’s disease, Nature Communications 3:1146
11. Kita, T. & Kita, H. (2011) Cholinergic and non-cholinergic mesopontine tegmental neurons projecting to the subthalamic nucleus in the rat. Eur J Neurosci. 33, 433-443
12. Kita H, Kita T (2011) Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia. J. Neurosci. 31(28):10311-10322
13. Kita T, Kita H (2012) The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: a single-axon tracing study in the rat. J. Neurosci. 32:5990-5999
14. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547-551
15. Nishibayashi H, Ogura M, Kakishita K, Tanaka S, Tachibana Y, Nambu A, Kita H, Itakura T (2011) Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery. Mov Disord 26(3):469-476
16. Sheets PL, Suter BA, Kiritani T, Chan CS, Surmeier DJ, Shepherd GM (2011) Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control. J. Neurophysiol 106(5):2216-2231
17. Sulzer D, Surmeier DJ (2012) Neuronal vulnerability, pathogenesis, and Parkinson's disease. Mov Disordety. Article first published online: 12 JUL 2012
18. Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT (2012) Physiological phenotype and vulnerability in Parkinson's disease. Cold Spring Harb Perspect Med 2(7): a009290
19. Surmeier DJ, Guzman JN, Sanchez-Padilla J, Schumacker PT (2011) The role of Ca2+  and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson's disease. Neuroscience 198:221-231
20. Tachibana Y, Iwamuro H, Kita H, Takada M, Nambu A (2011) Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia. Eur J Neurosci. 34(9):1470-1484
21. Wilson, C.J., Beverlin, B. II, and Netoff, T. (2011) Chaotic desynchronization as the therapeutic mechanism of deep brain stimulation. Front Syst Neurosci. 5:50.  PMCID: PMC31222072

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