Director: D. James Surmeier, Ph.D.
Title: Rhythmicity and Synchrony in the Basal Ganglia
Budget End Date: 7/31/2018
Our Center is focused on two major lines of study in Parkinson’s disease (PD) 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 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 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 NINDS-supported Phase III clinical trial with early stage PD patients is beginning this year. 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.
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
- Discovered that locus ceruleus (LC) noradrenergic neurons at risk in Parkinson’s disease have a similar physiological phenotype to that found in substantia nigra (SN) dopaminergic (DA) neurons. In both cell types, pacemaking associated Ca2+ entry through L-type channels increases mitochondrial oxidant stress. Also found that Ca2+ entry into mitochondria increases nitrosative stress in both LC and SN neurons through a mechanism that is sensitive to inhibitors of nitric oxide synthase. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Discovered that sustained systemic administration of isradipine at doses shown to be protective in animal models of PD elevates mitochondrial mass in SN dopaminergic neurons leading to a lowering of mitochondrial oxidant stress below that achieved by acute treatment. Mitochondrial mass was not altered in neighboring ventral tegmental area neurons or in LC neurons. In addition, it was found that sustained isradipine treatment does not increase the expression of other Ca2+ channels in SN dopaminergic neurons or alter pacemaking properties. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Completed functional mapping of pedunculopontine nucleus (PPN) glutamatergic synapses on SN DA neurons. These studies revealed PPN glutamatergic inputs are distributed along proximal, but not distal dendrites. Moreover, these synapses contain both AMPA and NMDA receptors. Characterization of STN synapses is ongoing. These studies are pertinent to network mechanisms underlying PD pathogenesis as well as network adaptations that might accelerate disease progression, NINDS PD2014 Basic Research Priority #3.
- Completed re-engineering of a high-throughput screen for Cav1.3 channel antagonists based upon HEK293 cells that co-express Cav1.3 channels and constitutively active Kir2.1 K+ channels. This allows membrane potential of HEK293 cells to be controlled during compound exposure, revealing voltage-dependent interactions of compounds with Cav1.3 channels. This approach has revealed clear structure-activity relationships for compounds at depolarized membrane potentials. Moreover, these studies have confirmed that a group of antagonists are acting as negative allosteric modulators, rather than channel blockers. These studies are relevant to NINDS PD2014 Translational Research priorities #7 and #8.
- Completed comprehensive study of how oscillatory mechanisms normally decorrelate firing in basal ganglia output neurons, and how this mechanism may break down in PD. These studies are pertinent to network mechanisms underlying PD pathogenesis as well as network adaptations that might accelerate disease progression, relevant to NINDS PD2014 Basic Research Priority #3.
- Completed experimental work showing that oscillator theory can predict the firing patterns of subthalamic neurons with dense synaptic drive. (PLoS Computational Biology. 10:e1003612. This approach will enable us to predict the population activity and oscillations in basal ganglia output neurons under conditions of correlated shared input. These studies are pertinent to network mechanisms underlying PD pathogenesis as well as network adaptations that might accelerate disease progression, NINDS PD2014 Basic Research Priority #3.
- 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, NINDS PD2014 Basic Research Priority #3.
- In PD models, abnormal hypoactivity in GPe neurons disinhibits cortical excitation of STN neurons. This leads to excessive activation of NMDA receptors and maladaptive cellular and synaptic plasticity, which promotes parkinsonian activity and motor dysfunction. Knocking down NMDA receptors with gene therapy ameliorates this pathology. This work is important for understanding network dysfunction in PD, NINDS PD2014 Basic Research Priority #3.
- 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 but not the STN. 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, NINDS Basic Research Priority #3.
- TH/CMV mito-roGFP mice
- TH/CMV mito-roGFP AAV (this 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 consequences of ATG7 deletion on mitochondrial function in dopaminergic neurons.
- Continue pre-clinical development of selective Cav1.3 channel antagonists.
- Characterize alterations in GPe regulation of striatal neurons in PD models.
- Determine whether pharmacogenomics approaches can restore STN activity in PD models and ameliorate symptoms.
- 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
- Sanchez-Padilla J, Guzman JN, Ilijic E, Kondapalli J, Galtieri DJ, Yang B, Schieber S, Oertel W, Wokosin D, Schumacker PT & Surmeier DJ (2014) Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nature Neuroscience 17(6):832-840. PMCID: PMC4131291.
- Wilson C.J., Barraza D, Troyer T, and Farries F.A. (2014) Predicting the responses of repetitively firing neurons to current noise. PLoS Comput. Biol. 10:e1003612. PMCID: PMC4014400
- Goldberg JA, Atherton JF & Surmeier DJ (2013) Spectral reconstruction of phase response curves reveals the synchronization properties of mouse globus pallidus neurons. Journal of Neurophysiology 110(10):2497-2506. PMCID: PMC3841869
- Dryanovski DI, Guzman JN, Xie Z, Galteri DJ, Volpicelli-Daley LA, Lee VM, Miller RJ, Schumacker PT & Surmeier DJ (2013) Calcium entry and alpha-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. The Journal of Neuroscience:33(24):10154-10164. PMCID: PMC3682382
- Kang S, Cooper G, Dunne SF, Luan CH, Surmeier DJ & Silverman RB (2013) Structure-activity relationship of N,N'-disubstituted pyrimidinetriones as Ca(V)1.3 calcium channel-selective antagonists for Parkinson's disease. Journal of Medicinal Chemistry 56(11):4786-4797.
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.