RT Journal Article SR Electronic T1 Dopamine D2 Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 5512 OP 5525 DO 10.1523/JNEUROSCI.5548-10.2011 VO 31 IS 14 A1 Bruno Rezende Souza A1 Marco Aurelio Romano-Silva A1 Vincent Tropepe YR 2011 UL http://www.jneurosci.org/content/31/14/5512.abstract AB An imbalance in dopamine-mediated neurotransmission is a hallmark physiological feature of neuropsychiatric disorders, such as schizophrenia. Recent evidence demonstrates that dopamine D2 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 D2 receptor activation acutely suppresses Akt activity by decreasing the level of pAkt(Thr308) in the larval zebrafish brain. This D2-dependent reduction in Akt activity negatively regulates larval movement and is distinct from a D1-dependent pathway with opposing affects on motor behavior. In addition, we show that D2-dependent suppression of Akt activity causes a late onset change in GSK3b activity, a known downstream target of Akt signaling. Finally, altered D2 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 D2 receptor signaling suppresses Akt-GSK3b activity, which regulates GABAergic neuron development and motor behavior.