Chia-Shan Wu1,2,3, Christopher P Jew4,5,6, Hao Sun4,5, Carlos J Ballester Rosado4,5,6, Hui-Chen Lu7,8,9,10. 1. The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA. cjwu@tamu.edu. 2. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA. cjwu@tamu.edu. 3. Department of Nutrition and Food Science, Texas A&M University, 123 Cater-Mattil, 2253 TAMU, College Station, TX, 77843, USA. cjwu@tamu.edu. 4. The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA. 5. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA. 6. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. 7. The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA. hclu@indiana.edu. 8. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA. hclu@indiana.edu. 9. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. hclu@indiana.edu. 10. Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th Street, Bloomington, IN, 47405, USA. hclu@indiana.edu.
Abstract
RATIONALE: A role of group I metabotropic glutamate receptor 5 (mGlu5) in regulating spontaneous locomotion and psychostimulant-induced hyperactivity has been proposed. OBJECTIVES: This study aims to determine if mGlu5 in GABAergic neurons regulates spontaneous or psychostimulant-induced locomotion. METHODS: We generated mice specifically lacking mGlu5 in forebrain GABAergic neuron by crossing DLX-Cre mice with mGlu5flox/flox mice to generate DLX-mGlu5 KO mice. The locomotion of adult mice was examined in the open-field assay (OFA) and home cage setting. The effects of the mGlu5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP), cocaine, and methylphenidate on acute motor behaviors in DLX-mGlu5 KO and littermate control mice were assessed in OFA. Striatal synaptic plasticity of these mice was examined with field potential electrophysiological recordings. RESULTS: Deleting mGlu5 from forebrain GABAergic neurons results in failure to induce long-term depression (LTD) in the dorsal striatum and absence of habituated locomotion in both novel and familiar settings. In a familiar environment (home cage), DLX-mGlu5 KO mice were hyperactive. In the OFA, DLX-mGlu5 KO mice exhibited initial hypo-activity, and then gradually increased their locomotion with time, resulting in no habituation response. DLX-mGlu5 KO mice exhibited almost no locomotor response to MPEP (40 mg/kg), while the same dose elicited hyperlocomotion in control mice. The DLX-mGlu5 KO mice also showed reduced hyperactivity response to cocaine, while they retained normal hyperactivity response to methylphenidate, albeit with delayed onset. CONCLUSION: mGlu5 in forebrain GABAergic neurons is critical to trigger habituation upon the initiation of locomotion as well as to mediate MPEP-induced hyperlocomotion and modulate psychostimulant-induced hyperactivity.
RATIONALE: A role of group I metabotropic glutamate receptor 5 (mGlu5) in regulating spontaneous locomotion and psychostimulant-induced hyperactivity has been proposed. OBJECTIVES: This study aims to determine if mGlu5 in GABAergic neurons regulates spontaneous or psychostimulant-induced locomotion. METHODS: We generated mice specifically lacking mGlu5 in forebrain GABAergic neuron by crossing DLX-Cre mice with mGlu5flox/flox mice to generate DLX-mGlu5 KO mice. The locomotion of adult mice was examined in the open-field assay (OFA) and home cage setting. The effects of the mGlu5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP), cocaine, and methylphenidate on acute motor behaviors in DLX-mGlu5 KO and littermate control mice were assessed in OFA. Striatal synaptic plasticity of these mice was examined with field potential electrophysiological recordings. RESULTS: Deleting mGlu5 from forebrain GABAergic neurons results in failure to induce long-term depression (LTD) in the dorsal striatum and absence of habituated locomotion in both novel and familiar settings. In a familiar environment (home cage), DLX-mGlu5 KO mice were hyperactive. In the OFA, DLX-mGlu5 KO mice exhibited initial hypo-activity, and then gradually increased their locomotion with time, resulting in no habituation response. DLX-mGlu5 KO mice exhibited almost no locomotor response to MPEP (40 mg/kg), while the same dose elicited hyperlocomotion in control mice. The DLX-mGlu5 KO mice also showed reduced hyperactivity response to cocaine, while they retained normal hyperactivity response to methylphenidate, albeit with delayed onset. CONCLUSION: mGlu5 in forebrain GABAergic neurons is critical to trigger habituation upon the initiation of locomotion as well as to mediate MPEP-induced hyperlocomotion and modulate psychostimulant-induced hyperactivity.
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