Lack of GPR88 Enhances Medium Spiny Neuron Activity and Alters Motor- And Cue-Dependent Behaviors

Nat Neurosci. 2012 Nov;15(11):1547-55. doi: 10.1038/nn.3239. Epub 2012 Oct 14.

Abstract

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.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Avoidance Learning / physiology
  • Benzylamines / pharmacology
  • Biophysics
  • Cells, Cultured
  • Chromones / pharmacology
  • Corpus Striatum / cytology
  • Cues*
  • Electric Stimulation
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Female
  • GABA Antagonists / pharmacology
  • Gene Expression Profiling
  • Green Fluorescent Proteins / genetics
  • In Vitro Techniques
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / genetics*
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Phosphinic Acids / pharmacology
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Receptors, G-Protein-Coupled / deficiency*
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism
  • Rotarod Performance Test
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester
  • Benzylamines
  • Chromones
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Gpr88 protein, mouse
  • Phosphinic Acids
  • Receptors, AMPA
  • Receptors, G-Protein-Coupled
  • Receptors, GABA-B
  • CGP 52432
  • Green Fluorescent Proteins
  • gamma-Aminobutyric Acid
  • glutamate receptor ionotropic, AMPA 1