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    Anatol Kreitzer, PhD

    TitleAssociate Professor
    SchoolUCSF School of Medicine
    DepartmentPhysiology
    Address1650 Owens St
    San Francisco CA 94107
    Phone415-734-2507
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      Collapse Overview 
      Collapse Overview
      Areas of Investigation
      The research in our laboratory is focused on understanding the mechanisms controlling cellular, synaptic, and circuit function in the basal ganglia that control motor planning, learning, and movement. Our long-term goal is to understand how neural activity and plasticity in these circuits shapes motor behavior and how neurological disorders such as Parkinson's disease (PD) and Huntington's disease (HD) affect synaptic, cellular, and circuit function in the basal ganglia.

      Significance
      The control of movement is among the most fundamental functions of the nervous system. The basal ganglia, and the striatum in particular, play a critical role in the selection and learning of appropriate actions. Individuals suffering from movement disorders such as PD or HD have profound difficulties performing appropriate movements, yet the relation between aberrant neural activity and motor problems is not well understood. A thorough knowledge of the mechanisms underlying circuit function in the basal ganglia, both in health and disease, will provide a framework that can be used to develop novel treatments for neurological disorders.

      Approaches
      To address the functional properties of basal ganglia motor circuits, our laboratory applies a variety of experimental approaches. We use whole-cell patch-clamp electrophysiology in brain slices, which allows us to record and analyze the properties of synaptic currents from individual neurons. Transgenic animals expressing molecular markers in specific subpopulations of neurons allow for the in vitro and in vivo identification and modification of basal ganglia circuit function. Optogenetic manipulations provide a tool for cell-type specific manipulations in vitro and in vivo. Additionally, we use genetic and pharmacological animal models of human disease, as well as a battery of behavioral testing procedures.

      Contributions
      Two parallel basal ganglia pathways have been described, which are proposed to exert opposing influences on motor function. According to this classical model, activation of the direct pathway facilitates movement and activation of the indirect pathway inhibits movement. Imbalances in these circuits are thought to contribute to motor deficits in PD and HD. However, because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. We have developed the capability to directly activate basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs). Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia, and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson’s disease, direct pathway activation completely rescued deficits in freezing, bradykinesia, and locomotor initiation. Our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

      Questions Addressed in Ongoing Studies

      What is the functional role of neural activity in direct and indirect pathway MSNs?
      How is neural activity in the direct and indirect pathways integrated in basal ganglia output nuclei?
      How do striatal microcircuits function to shape direct and indirect pathway output?
      What role does dopamine play in striatal microcircuit function?
      How does loss of dopamine impact basal ganglia circuit function?
      How does dopamine modulate synaptic plasticity in the striatum?
      How can we restore basal ganglia circuit function in the absence of dopamine, such as during PD?


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      Collapse Bibliographic 
      Collapse Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
      List All   |   Timeline
      1. Kharkwal G, Brami-Cherrier K, Lizardi-Ortiz JE, Nelson AB, Ramos M, Del Barrio D, Sulzer D, Kreitzer AC, Borrelli E. Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons. Neuron. 2016 Jul 6; 91(1):67-78. PMID: 27387649.
        View in: PubMed
      2. Lee HJ, Weitz AJ, Bernal-Casas D, Duffy BA, Choy M, Kravitz AV, Kreitzer AC, Lee JH. Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses. Neuron. 2016 Jul 20; 91(2):412-24. PMID: 27373834.
        View in: PubMed
      3. Roseberry TK, Lee AM, Lalive AL, Wilbrecht L, Bonci A, Kreitzer AC. Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia. Cell. 2016 Jan 28; 164(3):526-37. PMID: 26824660.
        View in: PubMed
      4. Parker PR, Lalive AL, Kreitzer AC. Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice. Neuron. 2016 Feb 17; 89(4):734-40. PMID: 26833136.
        View in: PubMed
      5. Gunaydin LA, Kreitzer AC. Cortico-Basal Ganglia Circuit Function in Psychiatric Disease. Annu Rev Physiol. 2016 Feb 10; 78:327-50. PMID: 26667072.
        View in: PubMed
      6. Donahue CH, Kreitzer AC. A Direct Path to Action Initiation. Neuron. 2015 Oct 21; 88(2):240-1. PMID: 26494272.
        View in: PubMed
      7. Adamantidis A, Arber S, Bains JS, Bamberg E, Bonci A, Buzsáki G, Cardin JA, Costa RM, Dan Y, Goda Y, Graybiel AM, Häusser M, Hegemann P, Huguenard JR, Insel TR, Janak PH, Johnston D, Josselyn SA, Koch C, Kreitzer AC, Lüscher C, Malenka RC, Miesenböck G, Nagel G, Roska B, Schnitzer MJ, Shenoy KV, Soltesz I, Sternson SM, Tsien RW, Tsien RY, Turrigiano GG, Tye KM, Wilson RI. Optogenetics: 10 years after ChR2 in neurons--views from the community. Nat Neurosci. 2015 Sep; 18(9):1202-12. PMID: 26308981.
        View in: PubMed
      8. Nelson AB, Bussert TG, Kreitzer AC, Seal RP. Striatal cholinergic neurotransmission requires VGLUT3. J Neurosci. 2014 Jun 25; 34(26):8772-7. PMID: 24966377; PMCID: PMC4069355.
      9. Nelson AB, Hammack N, Yang CF, Shah NM, Seal RP, Kreitzer AC. Striatal cholinergic interneurons Drive GABA release from dopamine terminals. Neuron. 2014 Apr 2; 82(1):63-70. PMID: 24613418; PMCID: PMC3976769.
      10. Nelson AB, Kreitzer AC. Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci. 2014; 37:117-35. PMID: 25032493; PMCID: PMC4416475.
      11. Freeze BS, Kravitz AV, Hammack N, Berke JD, Kreitzer AC. Control of basal ganglia output by direct and indirect pathway projection neurons. J Neurosci. 2013 Nov 20; 33(47):18531-9. PMID: 24259575; PMCID: PMC3834057.
      12. Wall NR, De La Parra M, Callaway EM, Kreitzer AC. Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron. 2013 Jul 24; 79(2):347-60. PMID: 23810541; PMCID: PMC3729794.
      13. Suberbielle E, Sanchez PE, Kravitz AV, Wang X, Ho K, Eilertson K, Devidze N, Kreitzer AC, Mucke L. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-ß. Nat Neurosci. 2013 May; 16(5):613-21. PMID: 23525040; PMCID: PMC3637871.
      14. Kravitz AV, Owen SF, Kreitzer AC. Optogenetic identification of striatal projection neuron subtypes during in vivo recordings. Brain Res. 2013 May 20; 1511:21-32. PMID: 23178332; PMCID: PMC3594574.
      15. Gittis AH, Kreitzer AC. Striatal microcircuitry and movement disorders. Trends Neurosci. 2012 Sep; 35(9):557-64. PMID: 22858522; PMCID: PMC3432144.
      16. Andrews-Zwilling Y, Gillespie AK, Kravitz AV, Nelson AB, Devidze N, Lo I, Yoon SY, Bien-Ly N, Ring K, Zwilling D, Potter GB, Rubenstein JL, Kreitzer AC, Huang Y. Hilar GABAergic interneuron activity controls spatial learning and memory retrieval. PLoS One. 2012; 7(7):e40555. PMID: 22792368; PMCID: PMC3390383.
      17. Nelson AB, Hang GB, Grueter BA, Pascoli V, Luscher C, Malenka RC, Kreitzer AC. A comparison of striatal-dependent behaviors in wild-type and hemizygous Drd1a and Drd2 BAC transgenic mice. J Neurosci. 2012 Jul 4; 32(27):9119-23. PMID: 22764221; PMCID: PMC3420343.
      18. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang WR, Kreitzer AC, Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell. 2012 Jul 6; 11(1):100-9. PMID: 22683203; PMCID: PMC3399516.
      19. Kravitz AV, Tye LD, Kreitzer AC. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci. 2012 Jun; 15(6):816-8. PMID: 22544310; PMCID: PMC3410042.
      20. Kravitz AV, Kreitzer AC. Striatal mechanisms underlying movement, reinforcement, and punishment. Physiology (Bethesda). 2012 Jun; 27(3):167-77. PMID: 22689792; PMCID: PMC3880226.
      21. Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012 Apr 27; 149(3):708-21. PMID: 22541439; PMCID: PMC3375906.
      22. Javier RM, Kreitzer AC. Dendritic architecture: form and function. Nat Neurosci. 2012 Apr; 15(4):503-5. PMID: 22449957.
        View in: PubMed
      23. Harwell CC, Parker PR, Gee SM, Okada A, McConnell SK, Kreitzer AC, Kriegstein AR. Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation. Neuron. 2012 Mar 22; 73(6):1116-26. PMID: 22445340; PMCID: PMC3551478.
      24. Lerner TN, Kreitzer AC. RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron. 2012 Jan 26; 73(2):347-59. PMID: 22284188; PMCID: PMC3269032.
      25. Gittis AH, Leventhal DK, Fensterheim BA, Pettibone JR, Berke JD, Kreitzer AC. Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. J Neurosci. 2011 Nov 2; 31(44):15727-31. PMID: 22049415; PMCID: PMC3226784.
      26. Lee JA, Liu L, Javier R, Kreitzer AC, Delaloy C, Gao FB. ESCRT-III subunits Snf7-1 and Snf7-2 differentially regulate transmembrane cargos in hESC-derived human neurons. Mol Brain. 2011; 4:37. PMID: 21975012; PMCID: PMC3197483.
      27. Gittis AH, Hang GB, LaDow ES, Shoenfeld LR, Atallah BV, Finkbeiner S, Kreitzer AC. Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine. Neuron. 2011 Sep 8; 71(5):858-68. PMID: 21903079; PMCID: PMC3170520.
      28. Kreitzer AC, Berke JD. Investigating striatal function through cell-type-specific manipulations. Neuroscience. 2011 Dec 15; 198:19-26. PMID: 21867745; PMCID: PMC3221791.
      29. Higley MJ, Gittis AH, Oldenburg IA, Balthasar N, Seal RP, Edwards RH, Lowell BB, Kreitzer AC, Sabatini BL. Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS One. 2011; 6(4):e19155. PMID: 21544206; PMCID: PMC3081336.
      30. Kravitz AV, Kreitzer AC. Optogenetic manipulation of neural circuitry in vivo. Curr Opin Neurobiol. 2011 Jun; 21(3):433-9. PMID: 21420852; PMCID: PMC3130851.
      31. Lerner TN, Kreitzer AC. Neuromodulatory control of striatal plasticity and behavior. Curr Opin Neurobiol. 2011 Apr; 21(2):322-7. PMID: 21333525; PMCID: PMC3092792.
      32. Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, Kreitzer AC. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010 Jul 29; 466(7306):622-6. PMID: 20613723; PMCID: PMC3552484.
      33. Gittis AH, Nelson AB, Thwin MT, Palop JJ, Kreitzer AC. Distinct roles of GABAergic interneurons in the regulation of striatal output pathways. J Neurosci. 2010 Feb 10; 30(6):2223-34. PMID: 20147549; PMCID: PMC2836801.
      34. Lerner TN, Horne EA, Stella N, Kreitzer AC. Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists. J Neurosci. 2010 Feb 10; 30(6):2160-4. PMID: 20147543; PMCID: PMC2830732.
      35. Quiroz C, Luján R, Uchigashima M, Simoes AP, Lerner TN, Borycz J, Kachroo A, Canas PM, Orru M, Schwarzschild MA, Rosin DL, Kreitzer AC, Cunha RA, Watanabe M, Ferré S. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway. ScientificWorldJournal. 2009; 9:1321-44. PMID: 19936569; PMCID: PMC2871285.
      36. Kreitzer AC. Physiology and pharmacology of striatal neurons. Annu Rev Neurosci. 2009; 32:127-47. PMID: 19400717.
        View in: PubMed
      37. Kreitzer AC, Malenka RC. Striatal plasticity and basal ganglia circuit function. Neuron. 2008 Nov 26; 60(4):543-54. PMID: 19038213; PMCID: PMC2724179.
      38. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6; 55(5):697-711. PMID: 17785178.
        View in: PubMed
      39. Singla S, Kreitzer AC, Malenka RC. Mechanisms for synapse specificity during striatal long-term depression. J Neurosci. 2007 May 9; 27(19):5260-4. PMID: 17494712.
        View in: PubMed
      40. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature. 2007 Feb 8; 445(7128):643-7. PMID: 17287809.
        View in: PubMed
      41. Kreitzer AC, Malenka RC. Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci. 2005 Nov 9; 25(45):10537-45. PMID: 16280591.
        View in: PubMed
      42. Kreitzer AC. Neurotransmission: emerging roles of endocannabinoids. Curr Biol. 2005 Jul 26; 15(14):R549-51. PMID: 16051162.
        View in: PubMed
      43. Foster KA, Kreitzer AC, Regehr WG. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse. Neuron. 2002 Dec 19; 36(6):1115-26. PMID: 12495626.
        View in: PubMed
      44. Kreitzer AC, Regehr WG. Retrograde signaling by endocannabinoids. Curr Opin Neurobiol. 2002 Jun; 12(3):324-30. PMID: 12049940.
        View in: PubMed
      45. Kreitzer AC, Carter AG, Regehr WG. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron. 2002 May 30; 34(5):787-96. PMID: 12062024.
        View in: PubMed
      46. Kreitzer AC, Regehr WG. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J Neurosci. 2001 Oct 15; 21(20):RC174. PMID: 11588204.
        View in: PubMed
      47. Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron. 2001 Mar; 29(3):717-27. PMID: 11301030.
        View in: PubMed
      48. Kreitzer AC, Gee KR, Archer EA, Regehr WG. Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator. Neuron. 2000 Jul; 27(1):25-32. PMID: 10939328.
        View in: PubMed
      49. Kreitzer AC, Regehr WG. Modulation of transmission during trains at a cerebellar synapse. J Neurosci. 2000 Feb 15; 20(4):1348-57. PMID: 10662825.
        View in: PubMed
      50. Dittman JS, Kreitzer AC, Regehr WG. Interplay between facilitation, depression, and residual calcium at three presynaptic terminals. J Neurosci. 2000 Feb 15; 20(4):1374-85. PMID: 10662828.
        View in: PubMed
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