DOPAMINERGIC AND MUSCARINIC SIGNALING IN THE STRIATUM

Summary

Principal Investigator: DALTON JAMES SURMEIER
Abstract: DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common neurodegenerative disorder, afflicting as many as one million Americans. The core psychomotor symptoms of the disease are attributable to the degeneration of dopaminergic neurons innervating the striatum. Treatment strategies for PD patients are limited, making it imperative that we gain a better understanding of how DA - and its loss in PD - shapes striatal function. There are profound experimental obstacles that have prevented us from gaining the kind of conceptual foothold we need to make real a translational impact for PD patients. Two critical obstacles are striatal cellular heterogeneity and the inaccessibility of the small, spiny dendrites of MSNs - the principal site of DA modulation - to experimental interrogation. In the last grant period, we have developed approaches necessary to overcome these obstacles. To overcome cellular heterogeneity, we have taken advantage of Bacterial Artificial Chromosome (BAC) transgenic mice in which D1 or D2 receptor-expressing MSNs are labeled with enhanced green fluorescent protein (eGFP). These mice have enabled electrophysiological study of the functional properties of identified MSNs in tissue slices, providing unprecedented insights into how these two principal cell types differ and adapt in PD models. To overcome the inaccessibility of MSN dendrites to conventional patch clamp techniques, we have gained expertise in two- photon laser scanning microscopy (2PLSM) and 2P laser uncaging (2PLU), which make even the fine distal dendrites of MSNs accessible to structural and functional study, creating a window into the striatal adaptations in PD. The studies proposed in this revised renewal application marshal these and other powerful new tools to attack fundamental gaps in our understanding of the striatal pathophysiology in PD. We propose three specific aims that build upon the results obtained in the last funding period: 1) To characterize intrinsic ionic mechanisms governing dendritic excitability and synaptic integration in striatal medium spiny neurons (MSNs). Our central hypothesis is that MSN dendrites are invested with Ca2+ and K+ channels that govern short-term processing of synaptic inputs and long-term changes in synaptic strength;2) To characterize the signaling mechanisms underlying the induction and expression of synaptic plasticity in MSNs. Our central hypothesis is that DA receptor signaling cascades are critical to the induction of bidirectional, Hebbian plasticity at corticostriatal glutamatergic synapses;3) To characterize MSN somatodendritic adaptations in animal models of Parkinson's disease. Our central hypothesis is that dysregulation of dendritic excitability and synaptic plasticity following the loss of DA triggers cell-type homeostatic adaptations in MSNs that are responsible for pathological activity patterns and motor deficits in PD. The insights gained from this work should promote the development of novel and powerful therapeutic strategies for PD.
Funding Period: 1996-02-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models
    Michelle Day
    Department of Physiology, 303 East Chicago Avenue, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Nat Neurosci 9:251-9. 2006
  2. pmc Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection
    D James Surmeier
    Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
    Curr Opin Neurobiol 19:621-8. 2009
  3. pmc MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons
    Xinyong Tian
    Department of Physiology Feinberg School of Medicine Northwestern University 303 E Chicago Ave, Chicago, IL 60611, USA
    Mol Cell Neurosci 44:94-108. 2010
  4. pmc Thalamic gating of corticostriatal signaling by cholinergic interneurons
    Jun B Ding
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Neuron 67:294-307. 2010
  5. pmc Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors
    Helen S Bateup
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:14845-50. 2010
  6. ncbi The role of dopamine in modulating the structure and function of striatal circuits
    D James Surmeier
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
    Prog Brain Res 183:149-67. 2010
  7. pmc Synaptically driven state transitions in distal dendrites of striatal spiny neurons
    Joshua L Plotkin
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    Nat Neurosci 14:881-8. 2011
  8. pmc Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease
    Kelly E Glajch
    Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60610, USA
    Behav Brain Res 230:309-16. 2012
  9. pmc Strain-specific regulation of striatal phenotype in Drd2-eGFP BAC transgenic mice
    C Savio Chan
    Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
    J Neurosci 32:9124-32. 2012
  10. pmc A feud that wasn't: acetylcholine evokes dopamine release in the striatum
    D James Surmeier
    Department of Physiology, Feinberg College of Medicine, Northwestern University, Chicago, IL 60611, USA
    Neuron 75:1-3. 2012

Detail Information

Publications27

  1. ncbi Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models
    Michelle Day
    Department of Physiology, 303 East Chicago Avenue, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Nat Neurosci 9:251-9. 2006
    ..3 L-type Ca(2+) channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease...
  2. pmc Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection
    D James Surmeier
    Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
    Curr Opin Neurobiol 19:621-8. 2009
    ....
  3. pmc MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons
    Xinyong Tian
    Department of Physiology Feinberg School of Medicine Northwestern University 303 E Chicago Ave, Chicago, IL 60611, USA
    Mol Cell Neurosci 44:94-108. 2010
    ..Taken together, these studies establish a translational framework within which striatal adaptations linked to the symptoms of Parkinson's disease can be explored...
  4. pmc Thalamic gating of corticostriatal signaling by cholinergic interneurons
    Jun B Ding
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Neuron 67:294-307. 2010
    ..This differential regulation of the corticostriatal circuitry provides a neural substrate for attentional shifts and cessation of ongoing motor activity with the appearance of salient environmental stimuli...
  5. pmc Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors
    Helen S Bateup
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:14845-50. 2010
    ..These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors...
  6. ncbi The role of dopamine in modulating the structure and function of striatal circuits
    D James Surmeier
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
    Prog Brain Res 183:149-67. 2010
    ..These tools also have enabled a rapid expansion of our understanding of the striatal adaptations in models of Parkinson's disease. This chapter highlights some of the major advances in these areas...
  7. pmc Synaptically driven state transitions in distal dendrites of striatal spiny neurons
    Joshua L Plotkin
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    Nat Neurosci 14:881-8. 2011
    ..This capacity not only changes our model of how up states are generated in SPNs, it also has fundamental implications for the associative process underlying action selection...
  8. pmc Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease
    Kelly E Glajch
    Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60610, USA
    Behav Brain Res 230:309-16. 2012
    ....
  9. pmc Strain-specific regulation of striatal phenotype in Drd2-eGFP BAC transgenic mice
    C Savio Chan
    Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
    J Neurosci 32:9124-32. 2012
    ..Thus, the use of inbred strains of mice that are hemizygous for the Drd2 BAC transgene provides a reliable tool for studying basal ganglia function...
  10. pmc A feud that wasn't: acetylcholine evokes dopamine release in the striatum
    D James Surmeier
    Department of Physiology, Feinberg College of Medicine, Northwestern University, Chicago, IL 60611, USA
    Neuron 75:1-3. 2012
    ..These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine "feud" over control of striatal circuitry...
  11. pmc Convergent cortical innervation of striatal projection neurons
    Geraldine J Kress
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    Nat Neurosci 16:665-7. 2013
    ..Contrary to expectation, direct and indirect pathway striatal spiny projection neurons responded to both intratelencephalic and pyramidal tract activation, arguing that these cortical networks innervate both striatal projection neurons...
  12. pmc Regulation of dendritic calcium release in striatal spiny projection neurons
    Joshua L Plotkin
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    J Neurophysiol 110:2325-36. 2013
    ..In contrast, mGluRs had no effect on the induction of long-term potentiation. Taken together, these results make clearer how coactivation of mGluRs and L-type Ca(2+) channels promotes the induction of activity-dependent LTD in SPNs. ..
  13. pmc Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the KV2.1 potassium channel
    Durga P Mohapatra
    Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, CA 95616 8519, USA
    Channels (Austin) 3:46-56. 2009
    ..1-containing channels. These studies together demonstrate a specific contribution of modulation of KV2.1 channels in the activity-dependent regulation of intrinsic neuronal excitability...
  14. pmc A translational profiling approach for the molecular characterization of CNS cell types
    Myriam Heiman
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA
    Cell 135:738-48. 2008
    ....
  15. pmc Differential excitability and modulation of striatal medium spiny neuron dendrites
    Michelle Day
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    J Neurosci 28:11603-14. 2008
    ..Together, these results suggest that normally D(2) MSN dendrites are more excitable than those of D(1) MSNs and that DA depletion exaggerates this asymmetry, potentially contributing to adaptations in PD models...
  16. ncbi Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C
    Yuan Chen
    Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA
    Neuron 49:409-20. 2006
    ..Modulation of slow inactivation by neurotransmitters acting through G protein-coupled receptors, PKA, and PKC is a flexible mechanism of cellular plasticity controlling the firing behavior of central neurons...
  17. ncbi Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons
    Zhongfeng Wang
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Neuron 50:443-52. 2006
    ..In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning...
  18. ncbi RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
    Jun Ding
    Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA
    Nat Neurosci 9:832-42. 2006
    ..These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease...
  19. pmc Ca1.2 and CaV1.3 neuronal L-type calcium channels: differential targeting and signaling to pCREB
    Hua Zhang
    Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Eur J Neurosci 23:2297-310. 2006
    ..3 channels play a more important role in pCREB signaling in striatal medium spiny neurons than in hippocampal neurons. Our results provide novel insights into the function of CaV1.2 and CaV1.3 L-type Ca2+ channels in the brain...
  20. ncbi D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons
    D James Surmeier
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA lt j
    Trends Neurosci 30:228-35. 2007
    ..These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function...
  21. ncbi Cholinergic modulation of Kir2 channels selectively elevates dendritic excitability in striatopallidal neurons
    Weixing Shen
    Department of Physiology and Institute of Neuroscience, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave, Chicago, Illinois 60611, USA
    Nat Neurosci 10:1458-66. 2007
    ..This cell type-specific enhancement of dendritic excitability is an essential trigger for synaptic pruning after dopamine depletion, as pruning was prevented by genetic deletion of M1 muscarinic receptors...
  22. pmc Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson's disease
    Stefano Taverna
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    J Neurosci 28:5504-12. 2008
    ..Moreover, this recurrent collateral network appears to be disrupted in Parkinson's disease models, potentially contributing to pathological alterations in MSN activity patterns and psychomotor symptoms...
  23. pmc Corticostriatal and thalamostriatal synapses have distinctive properties
    Jun Ding
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    J Neurosci 28:6483-92. 2008
    ....
  24. pmc Dichotomous dopaminergic control of striatal synaptic plasticity
    Weixing Shen
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Science 321:848-51. 2008
    ..In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms...
  25. pmc Dichotomous anatomical properties of adult striatal medium spiny neurons
    Tracy S Gertler
    Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    J Neurosci 28:10814-24. 2008
    ..Thus, rather than being an intrinsically homogenous population, striatal MSNs have dichotomous somatodendritic properties that mirror differences in their network connections and biochemistry...
  26. pmc FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity
    Marc Flajolet
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
    Nat Neurosci 11:1402-9. 2008
    ....
  27. pmc MicroRNA-128 governs neuronal excitability and motor behavior in mice
    Chan Lek Tan
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA
    Science 342:1254-8. 2013
    ..These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders. ..

Research Grants30

  1. TULANE NATIONAL PRIMATE RESEARCH CENTER
    L Lee Hamm; Fiscal Year: 2013
    ..abstract_text> ..
  2. Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc
    Jay A Gingrich; Fiscal Year: 2013
    ..The proposed Center would address an important public health question about long-term effects of SSRIs on the fetus and provide better understanding of how serotonin can influence brain maturation and behavior. ..
  3. GABA channels and dopamine in striatum
    Stefano Vicini; Fiscal Year: 2013
    ....
  4. Monoaminergic regulation of prefrontal cortex inhibition during adolescence
    Kuei Yuan Tseng; Fiscal Year: 2013
    ....
  5. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  6. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  7. Factors that govern the role of dopamine in striatal AMPAR plasticity
    Mark John Thomas; Fiscal Year: 2013
    ..We expect our studies to inform new guiding principles for dopamine modulation in health and disease. ..
  8. M1 and M4 mAChRs in striatum-implication in treatment of movement disorders
    Zixiu Xiang; Fiscal Year: 2013
    ....
  9. Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Striatal Funct
    Anatol Kreitzer; Fiscal Year: 2013
    ..The ultimate goal of these studies is to uncover novel therapeutic strategies for treating striatal-based brain disorders. ..
  10. Signaling regulation in the striatum in Parkinson's disease
    Eugenia V Gurevich; Fiscal Year: 2013
    ..The studies will pave the way to development of novel therapeutic approaches to control motor deficits in Parkinsons'disease and complications of L-DOPA therapy. ..
  11. Extrastriatal functions of dopamine
    THOMAS N WICHMANN; Fiscal Year: 2013
    ....
  12. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  13. Neuroimaging for Early Diagnosis of Manganese Toxicity in Humans and Rodents
    Ulrike Dydak; Fiscal Year: 2013
    ....
  14. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..