title: Dopamine D2 receptor activity modulates Akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae.
abstract: An imbalance in dopamine-mediated neurotransmission is a hallmark physiological feature of neuropsychiatric disorders, such as schizophrenia. Recent evidence demonstrates that dopamine D(2) receptors, which are the main target of antipsychotics, modulate the activity of the protein kinase Akt, which is known to be downregulated in the brain of patients with schizophrenia. Akt has an important role in the regulation of cellular processes that are critical for neurodevelopment, including gene transcription, cell proliferation, and neuronal migration. Thus, it is possible that during brain development, altered Akt-dependent dopamine signaling itself may lead to defects in neural circuit formation. Here, we used a zebrafish model to assess the direct impact of altered dopamine signaling on brain development and larval motor behavior. We demonstrate that D(2) receptor activation acutely suppresses Akt activity by decreasing the level of pAkt(Thr308) in the larval zebrafish brain. This D(2)-dependent reduction in Akt activity negatively regulates larval movement and is distinct from a D(1)-dependent pathway with opposing affects on motor behavior. In addition, we show that D(2)-dependent suppression of Akt activity causes a late onset change in GSK3b activity, a known downstream target of Akt signaling. Finally, altered D(2) receptor signaling, or direct inhibition of Akt activity, causes a significant decrease in the size of the GABAergic neuron population throughout most of the brain. Our observations suggest that D(2) receptor signaling suppresses Akt-GSK3b activity, which regulates GABAergic neuron development and motor behavior.
authors.affiliation: Department of Cell & Systems Biology, Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
authors.forename: Bruno Rezende
authors.initials: BR
authors.lastname: Souza
authors.forename: Marco Aurelio
authors.initials: MA
authors.lastname: Romano-Silva
authors.forename: Vincent
authors.initials: V
authors.lastname: Tropepe
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000166:cytology* / Q000254:growth & development; D050882:CREB-Binding Protein / Q000378:metabolism; D002452:Cell Count; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D007814:Larva / Q000502:physiology; D018613:Microscopy, Confocal / Q000379:methods; D009068:Movement / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D011810:Quinoxalines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C501521:Akt-I-1,2 compound; D001596:Benzylamines; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D011810:Quinoxalines; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; C501122:dlx5a protein, zebrafish; D049452:Green Fluorescent Proteins; D013912:Threonine; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D050882:CREB-Binding Protein; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine