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
- 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.
- 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
- 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
- Farries, M.A. and Wilson, C.J. (2012) Biophysical basis of the phase response curve of subthalamic neurons. J. Neurophysiol.
- 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
- 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
- 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
- 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
- Jaeger D, Kita H (2011) Functional connectivity and integrative properties of globus pallidus neurons. Neuroscience 198:44-53
- 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
- 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
- Kita H, Kita T (2011) Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia. J. Neurosci.
- 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
- 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
- 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
- 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
- Sulzer D, Surmeier DJ (2012) Neuronal vulnerability, pathogenesis, and Parkinson's disease. Mov Disordety. Article first published
online: 12 JUL 2012
- 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
- 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
- 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
- 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
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 Ca2+ channel in autonomous pacemaking increased the sensitivity of dopaminergic
neurons to mitochondrial toxins used to create models of PD. Subsequently, we have shown that Ca2+ 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 are in preclinical 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. These studies are identifying a number of potential targets for pharmacological or genetic intervention that
are currently being tested in animal models. These studies clearly hold the promise of powerful new therapies for late stage