Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors.
The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell type-specific deletion of the striatal signaling protein dopamine- and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.
Bateup
Helen S
HS
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Santini
Emanuela
E
Shen
Weixing
W
Birnbaum
Shari
S
Valjent
Emmanuel
E
Surmeier
D James
DJ
Fisone
Gilberto
G
Nestler
Eric J
EJ
Greengard
Paul
P
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000503:physiopathology; D005260:Female; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity; D007150:Immunohistochemistry; D007980:Levodopa / Q000633:toxicity; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D049452:Green Fluorescent Proteins; D007980:Levodopa; D003042:Cocaine; D006220:Haloperidol