title: Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice.
abstract: Movement suppression in Parkinson's disease (PD) is thought to arise from increased efficacy of the indirect pathway basal ganglia circuit, relative to the direct pathway. However, the underlying pathophysiological mechanisms remain elusive. To examine whether changes in the strength of synaptic inputs to these circuits contribute to this imbalance, we obtained paired whole-cell recordings from striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs) and optically stimulated inputs from sensorimotor cortex or intralaminar thalamus in brain slices from control and dopamine-depleted mice. We found that dopamine depletion selectively decreased synaptic strength at thalamic inputs to dMSNs, suggesting that thalamus drives asymmetric activation of basal ganglia circuitry underlying parkinsonian motor impairments. Consistent with this hypothesis, in vivo chemogenetic and optogenetic inhibition of thalamostriatal terminals reversed motor deficits in dopamine-depleted mice. These results implicate thalamostriatal projections in the pathophysiology of PD and support interventions targeting thalamus as a potential therapeutic strategy.
authors.affiliation: Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Philip R L
authors.initials: PR
authors.lastname: Parker
authors.affiliation: Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Arnaud L
authors.initials: AL
authors.lastname: Lalive
authors.affiliation: Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Physiology and Neurology, University of California San Francisco, CA 94158, USA. Electronic address: akreitzer@gladstone.ucsf.edu.
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior; D007839:Functional Laterality; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000293:injuries; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology*; D013569:Synapses / Q000502:physiology*; D013788:Thalamus / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018663:Adrenergic Agents; D018690:Excitatory Amino Acid Agonists; D018398:Homeodomain Proteins; D016202:N-Methylaspartate; D016627:Oxidopamine; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D050599:Vesicular Glutamate Transport Protein 2; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000099260:Empty Spiracles Homeobox Proteins; C493477:Slc17a6 protein, mouse
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