Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice

Philip R L Parker; Arnaud L Lalive; Anatol C Kreitzer

doi:10.1016/j.neuron.2015.12.038

Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice

Neuron. 2016 Feb 17;89(4):734-40. doi: 10.1016/j.neuron.2015.12.038. Epub 2016 Jan 28.

Authors

Philip R L Parker¹, Arnaud L Lalive², Anatol C Kreitzer³

Affiliations

¹ Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
² Gladstone Institutes, San Francisco, CA 94158, USA.
³ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic Agents / toxicity
Animals
Corpus Striatum / pathology*
Disease Models, Animal
Excitatory Amino Acid Agonists / pharmacology
Excitatory Postsynaptic Potentials / drug effects
Excitatory Postsynaptic Potentials / genetics
Exploratory Behavior
Functional Laterality
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Medial Forebrain Bundle / injuries
Mice
N-Methylaspartate / pharmacology
Neural Pathways / physiology*
Oxidopamine / toxicity
Parkinsonian Disorders / chemically induced
Parkinsonian Disorders / pathology*
Synapses / physiology*
Thalamus / pathology*
Transcription Factors / genetics
Transcription Factors / metabolism
Tyrosine 3-Monooxygenase / metabolism
Vesicular Glutamate Transport Protein 2 / genetics
Vesicular Glutamate Transport Protein 2 / metabolism
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

Adrenergic Agents
Excitatory Amino Acid Agonists
Homeodomain Proteins
Slc17a6 protein, mouse
Transcription Factors
Vesicular Glutamate Transport Protein 2
empty spiracles homeobox proteins
N-Methylaspartate
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Oxidopamine
Tyrosine 3-Monooxygenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding