Dopamine D₂Receptor 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.

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice

“…Among the evidence are the findings that Akt and GSK3 phosphorylation were modulated by D2/D3 receptor antagonists, but not D1 receptor antagonists [13], deletion of D2 receptors, but not D1 receptors, abolished amphetamine- and apomorphine-mediated regulation of Akt/GSK3, whereas D3 receptor knockout mice displayed reduced, but not abolished, dopamine-regulated Akt phosphorylation [18], treatment with quinpirole, a D2 receptor agonist, reduced the phosphorylation of Akt and GSK3, whereas raclopride, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, increased the phosphorylation of Akt and GSK3 in rat brain [19]. Furthermore, D2 receptor activation was also linked to Akt dephosphorylation in the developing zebrafish brain [20]. Thus, it is now well-established that D2 receptors signal to regulate the phosphorylation of Akt and GSK3 using a mechanism mediated by a β-arrestin-containing complex.…”

Zebrafish forebrain and temporal conditioning

“…In larval zebrafish, the developing putative dopamine regions start functioning 3-4 days post fertilization (dpf ), immediately after hatching [47]. Indeed, altering dopamine neurotransmission by exposure to D1 or D2 receptor agonists/antagonists affects locomotion in 5-dpf zebrafish [48]. In addition, it is interesting to note that the TH1-expressing region in the subpallium is near the border between the ventral pallium and dorsal subpallium that stretches from anterior to posterior into an elongated striped area (figure 2, the red area below the dashed line) [43].…”

Neurons on the Move: Migration and Lamination of Cortical Interneurons

“…Although there was no change in the total number of interneurons in the CP/MZ, the D 1 receptor knockout showed a significant decrease in the number of interneurons in the IZ/SVZ, whilst the D 2 receptor knockout exhibited an increase in interneurons in this domain [167]. A recent study investigating the downstream molecular mechanisms of D 2 receptor activation in zebrafish [174] has illustrated the conserved nature of this signalling pathway for interneuron development and the importance of maintaining neurotransmitter homeostasis to promote the correct migration and positioning of cortical interneurons. …”