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


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Director: D. James Surmeier, Ph.D.

Title: Rhythmicity and Synchrony in the Basal Ganglia

Website: http://physio.northwestern.edu/research/udall/index.html

Budget End Date: 7/31/2018

Central Theme

The Northwestern University Center is focused on two major lines of study in Parkinson’s disease (PD) with strong translational potential. The first focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the subthalamic nucleus (STN), the external segment of the globus pallidus (GP) and the substantia nigra pars reticulate (SNr). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified adaptations in the STN-GP-SNr network in PD models that could be responsible for this pathophysiology. Our research teams are pursuing and will attempt to translate these discoveries 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 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 coeruleus and dorsal motor nucleus of the vagus appear to have a 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 an NINDS-supported Phase III clinical trial with early stage PD patients began in 2014. In addition, our Center initiated efforts to identify new and more powerful disease modifying drugs. Selective antagonists of Cav1.3 channels that lack the cardiovascular side-effects of dihydropyridines are now in pre-clinical development.

Center Structure

The Northwestern University Udall Center brings together four principal investigators (PIs) from two research institutions (Northwestern University and University of Texas) with complementary expertise. The Center is directed by Dr. D. James Surmeier (Northwestern University). Project leaders are Drs. Surmeier, Mark Bevan (Northwestern University), Savio Chan (Northwestern University) and Charles Wilson (University of Texas, San Antonio). In addition to these 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

  • Developed quantitative calcium imaging techniques suitable for use with SNc dopaminergic neurons in ex vivo brain slices. These studies have revealed that cytosolic calcium concentration in the somatic compartment oscillates between 30 and 150 nM; distal dendritic calcium concentration is considerably higher, oscillating between 50 and 450 nM – a concentration high enough to activate a variety of enzymes, including calpain. The amplitude of this oscillation is controlled by SERCA, as positive allosteric modulators significantly diminish this oscillation. We also have developed and validated a Cav1.3 shRNA that preferentially reduces dendritic calcium oscillations
  • Developed optical calcium probes targeted to mitochondrial matrix and endoplasmic reticulum to monitor calcium content during pacemaking and synaptic stimulation of SNc dopaminergic neurons in ex vivo brain slices. These studies have revealed that calcium entry through Cav1 channels, ryanodine receptors and mitochondrial uniporter control matrix calcium content. These studies have confirmed the role of calcium-induced calcium release in mitochondrial matrix calcium regulation.
  • Continued screening of Cav1.3 selective antagonists. Discovered that the PYT compounds bind with high affinity to the dihydropyridine binding site of Cav1 channels. Discovered that this interaction is voltage-dependent; the affinity of these compounds increases with membrane hyperpolarization, rather than depolarization like dihydropyridines. Medicinal chemistry and computational approaches are being used to identify a selective negative allosteric modulator with voltage-dependence similar to that of dihydropyridines.
  • Continued characterization of the PPN glutamatergic input to SNc dopaminergic neurons; discovered that synaptic NMDA receptors have a GluN2D subunit, which dramatically limits calcium entry; a selective antagonist from Dr. Steven Traynelis has been validated in ex vivo slice experiments. These studies are pertinent to network mechanisms underlying PD pathogenesis as well as network adaptations that might accelerate disease progression
  • Completed theoretical study of interactions between coupled oscillators, allowing prediction of phase interactions for neurons with an arbitrarily complex set of subthreshold ion channels. This work is important for understanding the effect of synaptic coupling in basal ganglia output cell population.
  • Discovered in experimental PD that excessive motor cortical activation of STN NMDA receptors triggers GPe-STN inputs to strengthen abnormally and thus contribute to the emergence of pathological, correlated activity in the STN.
  • A novel class of neuron in the GPe has been identified. These neurons express Npas1 and project to both direct and indirect pathway striatal projection neurons. Using optogenetic approaches, we have found that the strength of this negative feedback pathway is strengthened in a mouse model of Parkinson’s disease. This work is important for understanding network dysfunction in PD.
  • In PD models, abnormal hypoactivity is observed selectively in Npas1+ GPe neurons but not PV+ GPe neurons. This work is important for understanding network dysfunction in PD.

Center Goals aligned with NINDS PD2014 Research Priorities

The above studies address the following NINDS PD2014 research priorities:

  • Basic Research Recommendation 3:  Understand how different cell populations change in their coding properties, firing patterns, and neural circuit dynamics over time; how these changes relate to behavior and motor control; and how therapeutic interventions may affect such changes.

  • Basic Research Recommendation 11: Advance our understanding of neural circuits, circuit analysis techniques PD animal models and optogenetic and related imaging technologies to improve existing therapies and generate next-generation therapies for PD.

 

Resources Available

  • TH/CMV mito-roGFP mice
  • TH/CMV mito-roGFP AAV
  • TH mito-GCaMP6-AAV*
  • TH Cav1.3 shRNA AAV*

*will be made available through Addgene

Plans for the Coming Years

  • Continue the characterization of the effects of nicotine on SNc dopaminergic neurons.
  • Characterize glutamatergic inputs to SNc dopaminergic neurons from STN and PPN.
  • Characterize the effects of GABAergic input to SNc dopaminergic neurons.
  • Continue the characterization of how chronic Cav1 channel antagonism on SNc dopaminergic neurons remodels intrinsic excitability and mitochondrial function.
  • Continue pre-clinical development of selective Cav1.3 channel antagonists.
  • Continue the characterize alterations in GPe regulation of striatal neurons in PD models.
  • Characterize glutamatergic inputs to identified GPe neurons
  • Determine the relative contribution of striatal and cortical inputs to the abnormal frequency and pattern of STN-GPe network activity in PD models.
  • Determine whether chemogenetic restoration of intrinsic STN activity ameliorates motor dysfunction in PD models.
  • Determine how direct dopaminergic neuromodulation of the STN influences cortical patterning of the STN.
  • Simulate the effects of shared rhythmic (beta-frequency) input to SNr neurons in PD. We are also using our oscillator theory approach to predict the resulting firing pattern across the population of output neurons to understand pathological correlated firing

Select Recent Publications

Cooper G., Lasser-Katz E., Simchovitz A., Sharon R., Soreq H., Surmeier D.J., Goldberg J.A. Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus. J Neurophysiology, 2015. 114(3): 1513-20. PMCID: PMC4561632 [Available on 2016-09-01].

Hernández VM, Hegeman DJ, Cui Q, Kelver DA, Fiske MP, Glajch KE, Huang TY, Justice NJ, Chan CS. Paravalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus. J Neurosci, 2015, 35(34):11830 –11847. PMCID: PMC4549397 [Available on 2016-02-26].

Chu HY, Atherton JF, Wokosin D, Surmeier DJ, Bevan MD. Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron, 2015, 85: 364-76. PMCID: PMC4304914.

Wilson CJ. Oscillators and Oscillations in the Basal Ganglia. Neuroscientist, 2014, pii: 1073858414560826. [Epub ahead of print]. PMCID: PMC4454624 [Available on 2016-06-01].

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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 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 PD patients.

 

Last Modified March 8, 2016