Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice.
Degeneration of dopamine (DA) neurons in Parkinson's disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy.
Department of Neurology, Columbia University, New York, NY 10032, USA.
Anders
A
Borgkvist
Department of Pharmacology, Columbia University, New York, NY 10032, USA.
Elizabeth M
EM
Avegno
Department of Pharmacology, Columbia University, New York, NY 10032, USA.
Minerva Y
MY
Wong
Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Mazen A
MA
Kheirbek
Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Mark S
MS
Sonders
Department of Neuroscience, Columbia University, New York, NY 10032, USA.
Rene
R
Hen
Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Pharmacology, Columbia University, New York, NY 10032, USA; Department of Psychiatry, Columbia University, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: ds43@cumc.columbia.edu.
David
D
Sulzer
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D000075402:Channelrhodopsins; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D059330:GABAergic Neurons / Q000502:physiology*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D013378:Substantia Nigra / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018663:Adrenergic Agents; D001426:Bacterial Proteins; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; C073804:FM1 43; D018682:GABA Agents; D008164:Luminescent Proteins; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D011810:Quinoxalines; C054562:yellow fluorescent protein, Bacteria; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D004298:Dopamine