The Morris K. Udall Center of Excellence for Parkinson's Disease 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: Director D. James Surmeier, PhD (Northwestern University), Mark D. Bevan, PhD (Northwestern University), Charles J. Wilson, PhD (University of Texas, San Antonio), Hitoshi Kita, PhD (University of Tennessee), Pavel Osten, MD, PhD (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 pacemaking in vulnerable dopaminergic neurons is not dependent upon L-type Ca²⁺ channels as previously thought. This implies that neuroprotective therapies in early stage PD based upon L-type channel antagonism should not compromise the function of remaining neurons.
• 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.
• The discovery that dopamine depletion induces a down-regulation of HCN channels in globus pallidus neurons, leading to a loss of autonomous activity. This activity is necessary to prevent the emergence of pathological rhythmic bursting thought to underlie PD motor symptoms. Viral delivery of the down-regulated ion channel subunit was able to restore autonomous pacemaking. The behavioral consequences of the gene therapy are now being assessed in mouse models of late stage PD.

 

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 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.
• We will continue our gene therapy work aimed at restoring autonomous activity to GP neurons in a mouse model of PD. The primary goal at this point will be to determine whether there is behavioral recovery following re-establishment of pacemaking. We will also characterize tissue from human patients to determine whether there is a selective down-regulation of HCN channel genes in late stage PD patients.
• With the help of ARRA funds, we plan to test the hypothesis that non-dopaminergic neurons at risk in PD share the calcium-dependent phenotype of vulnerable dopaminergic neurons. Our initial focus will be on neurons in the locus ceruleus and the dorsal motor nucleus of the vagus.

 

Select Recent Publications

Atherton JF, Wokosin DL, Ramanathan S, Bevan MD (2008) Autonomous initiation and propagation of action potentials in neurons of the subthalamic nucleus. J Physiol 586:5679-5700.

Baufreton J, Bevan MD (2008) D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus. J Physiol 586:2121-2142.

Day M, Wokosin D, Plotkin JL, Tian X, Surmeier DJ (2008) Differential excitability and modulation of striatal medium spiny neuron dendrites. J Neurosci 28:11603-11614.

Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ (2008) Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord 14 Suppl 2:S112-115.

Ramanathan S, Tkatch T, Atherton JF, Wilson CJ, Bevan MD (2008) D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels. J Neurophysiol 99:442-459.

Rehberg M, Lepier A, Solchenberger B, Osten P, Blum R (2008) A new non-disruptive strategy to target calcium indicator dyes to the endoplasmic reticulum. Cell Calcium 44:386-399.

Rehberg M, Lepier A, Solchenberger B, Osten P, Blum R (2008) A new non-disruptive strategy to target calcium indicator dyes to the endoplasmic reticulum. Cell Calcium.

Tachibana Y, Kita H, Chiken S, Takada M, Nambu A (2008) Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys. Eur J Neurosci 27:238-253.

Taverna S, Ilijic E, Surmeier DJ (2008) Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson's disease. J Neurosci 28:5504-5512.

Teagarden M, Atherton JF, Bevan MD, Wilson CJ (2008) Accumulation of cytoplasmic calcium, but not apamin-sensitive afterhyperpolarization current, during high frequency firing in rat subthalamic nucleus cells. J Physiol 586:817-833.

Teagarden M, Atherton JF, Bevan MD, Wilson CJ (2008) Accumulation of cytoplasmic calcium, but not apamin-sensitive afterhyperpolarization current, during high frequency firing in rat subthalamic nucleus cells. J Physiol 586:817-833.

Baufreton J, Kirkham E, Atherton JF, Menard A, Magill PJ, Bolam JP, Bevan MD (2009) Sparse but selective and potent synaptic transmission from the globus pallidus to the subthalamic nucleus. J Neurophysiol 102:532-545.

Chan CS, Gertler TS, Surmeier DJ (2009) Calcium homeostasis, selective vulnerability and Parkinson's disease. Trends Neurosci 32:249-256.

Deister CA, Chan CS, Surmeier DJ, Wilson CJ (2009) Calcium-activated SK channels influence voltage-gated ion channels to determine the precision of firing in globus pallidus neurons. J Neurosci 29:8452-8461.

Dodla R, Wilson CJ (2009) Asynchronous response of coupled pacemaker neurons. Phys Rev Lett 102:068102.

Goldberg JA, Teagarden MA, Foehring RC, Wilson CJ (2009) Nonequilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons. J Neurosci 29:8396-8407.

Grinevich V, Kolleker A, Eliava M, Takada N, Takuma H, Fukazawa Y, Shigemoto R, Kuhl D, Waters J, Seeburg PH, Osten P (2009) Fluorescent Arc/Arg3.1 indicator mice: A versatile tool to study brain activity changes in vitro and in vivo. J Neurosci Methods.

Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ (2009) Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 29:11011-11019.

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.

Surmeier DJ (2009) A lethal convergence of dopamine and calcium. Neuron 62:163-164.

Watanabe K, Kita T, Kita H (2009) Presynaptic actions of D2-like receptors in the rat cortico-striato-globus pallidus disynaptic connection in vitro. J Neurophysiol 101:665-671.

 

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. The good news is that this channel can be re-introduced using gene therapy. We have been able to show that re-introduction of this gene, normalizes the activity of globus pallidus neurons in PD models. The next step is to see if it helps to restore normal motor function. This work holds the promise of a powerful new therapy for late stage PD patients that is as good or better than deep brain stimulation without having an indwelling electrode.