Abstract
The motor symptoms of Parkinson's disease (PD) are thought to stem from an imbalance in the activity of striatal direct- and indirect-pathway spiny projection neurons (SPNs). Disease-induced alterations in the activity of networks controlling SPNs could contribute to this imbalance. One of these networks is anchored by the parafascicular nucleus (PFn) of the thalamus. To determine the role of the PFn in striatal PD pathophysiology, optogenetic, chemogenetic, and electrophysiological tools were used in ex vivo slices from transgenic mice with region-specific Cre recombinase expression. These studies revealed that in parkinsonian mice, the functional connectivity of PFn neurons with indirect pathway SPNs (iSPNs) was selectively enhanced by cholinergic interneurons acting through presynaptic nicotinic acetylcholine receptors (nAChRs) on PFn terminals. Attenuating this network adaptation by chemogenetic or genetic strategies alleviated motor-learning deficits in parkinsonian mice, pointing to a potential new therapeutic strategy for PD patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 444-458.e6 |
| Journal | Neuron |
| Volume | 101 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 6 2019 |
Bibliographical note
Funding Information:The authors would like to thank Daniel Galtieri for development of a Python program for analysis, Sasha Ulrich for general laboratory management, Savio Chan for a gift of Cre-off ChR2 virus, and members of the Surmeier lab for comments on the manuscript. This work was supported by a Parkinson’s Disease Foundation Fellowship to A.T.; a Flanagan Fellowship to Y.D.; and grants from the JPB Foundation , the IDP Foundation, and the NIH ( NS 34696 , NS 54850 ) to D.J.S.
Publisher Copyright:
© 2019 Elsevier Inc.
Keywords
- Parkinson's disease
- indirect pathway spiny projection neuron
- motor learning
- nicotinic acetylcholine receptor
- parafascicular nucleus
- presynaptic modulation
- striatal cholinergic interneuron