Director: D. James Surmeier, PhD
Rhythmicity and Synchrony in the Basal Ganglia
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.
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 pathological activity. Our research teams are pursuing these discoveries and will attempt to translate it into new therapeutic approaches for late stage PD patients.
Our center is also focused on the causes of PD in the hope of developing disease modifying therapies. This effort has focused on the factors underlying selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc), whose death in PD is responsible for akinesia, bradykinesia and rigidity. These studies led to the recognition that autonomous activity and the engagement of voltagegated calcium channels created a basal mitochondrial stress in at-risk SNc dopaminergic neurons, increasing their vulnerability to genetic mutations and environmental toxins. Importantly, these studies also suggest that vulnerability can be diminished with a drug that is approved for human use, an inference supported by epidemiological studies. These observations led to an NINDS-supported Phase III clinical trial in early stage PD patients with the drug isradipine that will be completed in 2018. While continuing our effort to understand how these intrinsic mechanisms, as well as synaptic mechanisms, contribute to pathogenesis, we have also initiated efforts to identify new and more powerful disease modifying drugs that lack significant side-effects. More recently, our team has expanded our study of pathogenesis to pursue the linkage between psychostimulant use and PD risk. This effort has uncovered an unexpected connection between mitochondria, calcium and dopamine in the axon terminals of SNc dopaminergic neurons that might drive terminal degeneration with prolonged psychostimulant use. This work also has identified a strategy for alleviating degeneration with FDA approved drugs.
Recent Significant Advances
- Developed a strategy for monitoring mitophagy in SNc dopaminergic neurons in vivo using viral delivery of a dopaminergic neuron specific mito-Keima expression construct. Using this approach, we have demonstrated that 1) mitophagy is elevated in SNc dopaminergic neurons in vivo and 2) systemic administration of isradipine significantly diminishes mitophagy, elevates mitochondrial mass and lowers mitochondrial oxidant stress in SNc dopaminergic neurons in vivo. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Discovered that levodopa, methamphetamine, and amphetamine increase mitochondrial oxidant stress in axon terminals of SNc dopaminergic neurons in mice. This oxidant stress was exacerbated by activity-dependent calcium entry through Cav1 channels, which have recently been shown to participate in terminal dopamine release. The dopamine triggered mitochondrial stress was alleviated by monoamine oxidase inhibitors, suggesting a novel mechanism of dopamine metabolism. The same basic mechanisms have been found in human dopaminergic neurons derived from induced pluripotent stem cells. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Validated quantitative calcium imaging techniques suitable for use with SNc dopaminergic neurons (and other neurons) in ex vivo brain slices. These studies have led to quantitative estimates of cytosolic calcium concentration in different subcellular compartments of SNc dopaminergic neurons, which is critical to understanding the biochemical consequences of calcium entry during pacemaking and pathogenic mechanisms. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Validated 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. These studies are relevant to NINDS PD2014 Translational Research Priorities #7 and 8.
- Discovered that pedunculopontine nucleus (PPN) glutamatergic synapses on SNc dopaminergic neurons are capable of driving phasic burst spiking. This is accomplished by strong excitatory synapses on the proximal dendrites, including the axon bearing axon dendrite. Interestingly, this burst generation mechanism is independent of NMDA receptors, long thought to be necessary for burst generation and contributors to PD pathogenesis. 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.
- Discovered that phasic activation of GABAergic inputs to SNc dopaminergic neurons induced a suppression of SK channel opening and an increased propensity to spike in bursts, but not membrane hyperpolarization. GABAB receptor signaling mediated this effect. This work is important for understanding network dysfunction in PD, NINDS Basic Research Priority #3.
- Discovered that PYT inhibitors of Cav1.3 channels interact with the dihydropyridine binding site, conferring voltage-dependence to the interaction. Medicinal chemistry and computational approaches are being used to modify the PYT backbone in an effort to identify a molecular with selectivity and appropriate voltage-dependence. These studies are relevant to NINDS PD2014 Translational Research priorities #7 and #8.
- Discovered that following loss of SNc dopamine neurons, hyperactivity of the indirect pathway leads to: disinhibition of the STN, excessive activation of STN NMDA receptors, downregulation of hyperdirect pathway cortico-STN inputs, upregulation of indirect pathway pallido-STN inputs, and loss of autonomous STN activity. Together these maladaptive alterations are likely to contribute to the excessive patterning and synchronization of the STN in PD. This work is important for understanding network dysfunction in PD, NINDS Basic Research Priority #3.
- Discovered in parkinsonian mice that knocking down STN NMDA receptors prevented maladaptive plasticity of the STN. Interestingly, this genetic manipulation increased the strength of hyperdirect pathway cortico-STN inputs and decreased the strength of indirect pathway pallido-STN inputs relative to those in dopamine-intact mice. These alterations are predicted to worsen motor dysfunction in parkinsonian mice but were in fact therapeutic, arguing that a reduction in pallido-STN synaptic patterning may be critical for therapy. This work is important for understanding network dysfunction in PD and suggests novel therapeutic approaches for treating the motor symptoms of advanced PD, NINDS Basic Research Priority #3.
- Discovered that chemogenetic rescue of intrinsic, decorrelating STN activity in parkinsonian mice ameliorates their motor dysfunction. This work is important for understanding network dysfunction in PD and suggests novel therapeutic approaches for treating the motor symptoms of advanced PD, NINDS Basic Research Priority #3.
- Identified a desynchronizing effect of recurrent inhibition in the basal ganglia output neurons in the substantia nigra pars reticulata (SNr), which should normally mitigate the synchronizing effects of beta oscillations. Also determined that this function of SNr cells is normal in 6-OHDA animals, arguing that intra-nuclear mechanisms do not contribute to the emergence of synchrony in PD. This work is important for understanding the effect of synaptic coupling in basal ganglia output cell population, NINDS PD2014 Basic Research Priority #3.
- Developed a way of producing synchronized beta oscillations in a large population of SNr cells using channelrhodopsin. This pathological activity pattern, which is thought to contribute to motor symptoms in PD, is now being manipulated by stimulation of the STN or GPe. This work is important for understanding the effect of synaptic coupling in basal ganglia output cell population, NINDS PD2014 Basic Research Priority #3.
- Discovered that the GABAergic pallidostriatal projection mediated by Npas1+ neurons suppresses the response of spiny projection neurons (SPNs) to cortical excitatory synaptic input through both direct and indirect mechanisms. This work is important for understanding network dysfunction in PD, NINDS Basic Research Priority #3.
- Discovered that indirect pathway SPNs preferentially innervate prototypical, PV+ GPe neurons, whereas direct pathway SPNs preferentially innervate arkypallidal, Npas1+ GPe neurons. These synaptic connections are altered in parkinsonian mice. This work is important for understanding network dysfunction in PD, NINDS PD2014 Basic Research Priority #3.