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A C Meirsman1,2, Sami Ben Hamida3, E Clarke3

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The orphan receptor GPR88 influences distinct behaviors by acting on D1 and D2 receptor medium spiny neurons (MSNs). GPR88 in D2R-MSNs impacts social behavior and motor control, while in D1R-MSNs, it affects habituation and motor learning.

Keywords:
anxietylocomotionmedium spiny neuronmotor coordinationorphan GPCRstriatum

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Area of Science:

  • Neuroscience
  • Behavioral Neuroscience
  • Receptor Biology

Background:

  • The orphan receptor GPR88 is highly expressed in medium spiny neurons (MSNs) within the striatum.
  • GPR88 is implicated in various striatal-dependent functions, with total gene deletion affecting anxiety, locomotion, and motor coordination.
  • Medium spiny neurons express either D1 receptors (D1R) or D2 receptors (D2R), playing opposing roles in neural circuits.

Purpose of the Study:

  • To elucidate the specific roles of GPR88 in D1R-MSNs versus D2R-MSNs.
  • To differentiate the behavioral contributions of GPR88 in these two distinct neuronal populations.

Main Methods:

  • Generation and comparison of conditional GPR88 knockout mice: D1R-Gpr88 KO and A2A R-Gpr88 KO (targeting D2R-MSNs).
  • Behavioral analysis of conditional KO mice alongside a total Gpr88 KO (CMV-Gpr88 mice).
  • Assessment of anxiety-like behaviors, locomotion, stereotypies, social interaction, and motor coordination using established assays (marble burying, open field, rotarod).

Main Results:

  • Most phenotypes observed in total Gpr88 KO mice were replicated in D2R-MSN specific KO mice, including reduced anxiety, increased social interaction, enhanced locomotion and stereotypies, and impaired motor coordination.
  • Reduced habituation and motor skill learning were observed in total KO and D1R-MSN specific KO mice, but not in D2R-MSN specific KO mice.
  • D1R-MSN specific KO mice exhibited no other significant behavioral alterations beyond habituation and learning deficits.

Conclusions:

  • GPR88 differentially modulates the function of D1R-MSNs and D2R-MSNs, leading to distinct behavioral outcomes.
  • GPR88 in D2R-MSNs is crucial for regulating defensive behaviors, social interactions, locomotion, and motor coordination.
  • GPR88 in D1R-MSNs plays a role in novelty habituation and the acquisition of motor skills.