Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors.
The striatum regulates motor control, reward and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G protein-coupled receptor GPR88 is robustly expressed in MSNs and is regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. We found that, in the absence of GPR88, MSNs showed increased glutamatergic excitation and reduced GABAergic inhibition, which promoted enhanced firing rates in vivo, resulting in hyperactivity, poor motor coordination and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescued the molecular and electrophysiological properties and normalized behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.
Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, Washington, USA.
Albert
A
Quintana
Elisenda
E
Sanz
Wengang
W
Wang
Granville P
GP
Storey
Ali D
AD
Güler
Matthew J
MJ
Wanat
Bryan A
BA
Roller
Anna
A
La Torre
Paul S
PS
Amieux
G Stanley
GS
McKnight
Nigel S
NS
Bamford
Richard D
RD
Palmiter
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001596:Benzylamines / Q000494:pharmacology; D001703:Biophysics; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D003463:Cues; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010721:Phosphinic Acids / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency*; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001596:Benzylamines; D002867:Chromones; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D049452:Green Fluorescent Proteins; D010721:Phosphinic Acids; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; C485998:Gpr88 protein, mouse; C083008:CGP 52432