ZFIN ID: ZDB-PUB-110512-2
Dopamine d2 receptor activity modulates akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae
de Souza, B.R., Romano-Silva, M.A., and Tropepe, V.
Date: 2011
Source: The Journal of neuroscience : the official journal of the Society for Neuroscience   31(14): 5512-5525 (Journal)
Registered Authors: Souza, Bruno Rezende, Tropepe, Vincent
Keywords: none
MeSH Terms:
  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal
  • Benzylamines/pharmacology
  • Brain/cytology*
  • Brain/growth & development
  • CREB-Binding Protein/metabolism
  • Cell Count
  • Dopamine/metabolism
  • Dopamine/pharmacology
  • Dopamine Agents/pharmacology
  • Drug Interactions
  • Enzyme Inhibitors/pharmacology
  • Enzyme-Linked Immunosorbent Assay/methods
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Expression Regulation, Developmental/physiology
  • Glycogen Synthase Kinase 3/metabolism
  • Green Fluorescent Proteins/genetics
  • Homeodomain Proteins/genetics
  • Larva/physiology
  • Microscopy, Confocal/methods
  • Movement/physiology*
  • Neurons/drug effects
  • Neurons/metabolism*
  • Oncogene Protein v-akt/metabolism*
  • Phosphorylation
  • Quinoxalines/pharmacology
  • Receptors, Dopamine D2/metabolism*
  • Signal Transduction/drug effects
  • Signal Transduction/physiology*
  • Threonine/metabolism
  • Transcription Factors/genetics
  • Tyrosine 3-Monooxygenase/metabolism
  • Zebrafish
  • gamma-Aminobutyric Acid/metabolism*
PubMed: 21471388 Full text @ J. Neurosci.
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.
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