Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion

Jose de Jesus Aceves Buendia, Lior Tiroshi, Wei Hua Chiu, Joshua A. Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The widely held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre-dependent channelrhodopsin-2 (ChR2) the PfN of Vglut2-Cre mice that were dopamine-depleted with 6-hydroxydopamine (6-OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6-OHDA-treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6-OHDA lesions failed to affect short-term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA-to-AMPA ratios at PfN synapses—that were significantly larger than NMDA-to-AMPA ratios at cortical synapses—were reduced by 6-OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D 5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short-term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de-potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.

Original languageAmerican English
Pages (from-to)824-833
Number of pages10
JournalEuropean Journal of Neuroscience
Volume49
Issue number6
DOIs
StatePublished - Mar 2019

Bibliographical note

Publisher Copyright:
© 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Keywords

  • 6-OHDA
  • basal ganglia
  • optogenetics
  • slice electrophysiology

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