Dopamine Receptor Activation Modulates GABA Neuron Migration from the Basal Forebrain to the Cerebral Cortex

Crandall, James E.; McCarthy, Deirdre M.; Araki, Kiyomi Y.; Sims, John R.; Ren, Jingyi; Bhide, Pradeep G.

doi:10.1523/jneurosci.5124-06.2007

Cited by 120 publications

(108 citation statements)

References 59 publications

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“…DA is known to regulate mammalian neural progenitor proliferation (Popolo et al, 2004;McCarthy et al, 2007) and migration of GABAergic neurons in the telencephalon (Crandall et al, 2007). In addition, deficiencies and specific polymorphisms in Akt1 affect the structure of mammalian cortical regions that are modulated by DA pathways (Lai et al, 2006;Tan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it was recently shown that a balance between D 1 and D 2 receptor signaling could control the migration of newly generated GABAergic neurons in the forebrain (Crandall et al, 2007). These findings have important implications for understanding the neurodevelopmental basis of several behavioral disorders, for which alterations in DA and GABAergic neuronal systems have been implicated (Benes and Berretta, 2001;Seeman, 2006;Souza et al, 2006).…”

Section: Introductionmentioning

confidence: 97%

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Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Souza¹,

Romano-Silva²,

Tropepe³

2011

J. Neurosci.

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Souza¹,

Romano-Silva²,

Tropepe³

2011

J. Neurosci.

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“…Recently we showed that dopamine receptor activation modulates migration of GABA neurons from the embryonic mouse striatum to the cerebral cortex [5]. Activation of the D1R promoted the migration whereas activation of the D2R decreased it suggesting that the ability of the neurons to migrate to the cortex may be influenced by the balance of expression between D1-like and D2-like receptors.…”

Section: Discussionmentioning

confidence: 99%

Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development

2007

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The outcome of dopaminergic signaling and effectiveness of dopaminergic drugs depend on the relative preponderance of each of the five dopamine receptors in a given brain region. The separate contribution of each receptor to overall dopaminergic tone is difficult to establish at a functional level due to lack of receptor subtype specific pharmacological agents. A surrogate for receptor function is receptor protein or mRNA expression. We examined dopamine receptor mRNA expression by quantitative reverse transcription real-time PCR in the striatum, globus pallidus, frontal cortex and cingulate cortex of embryonic and postnatal mice. Samples of each region were collected by laser capture microdissection. D1-and D2-receptor mRNAs were the most abundant in all the regions of the mature brain. The D1-receptor was predominant over the D2-receptor in the frontal and cingulate cortices whereas the situation was reversed in the striatum and globus pallidus. In the proliferative domains of the embryonic forebrain, D3-, D4-and D5-receptors were predominant. In the corpus striatum and cerebral cortex, the D3-and D4-receptors were the only receptors that showed marked developmental regulation. By analyzing D1 receptor protein expression, we show that developmental changes in mRNA expression reliably translate into changes in protein levels, at least for the D1-receptor.

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“…Activation of dopamine receptors influences cell proliferation in the lateral ganglionic eminence (LGE) and the neuroepithelium of the frontal cortex in embryonic mice [39,43,72,73] and in the subventricular zone and hippocampal dentate gyrus in the adult mice [18,22,64]. Dopamine receptor activation also influences GABA neuron migration from the basal forebrain to the cerebral cortex [13] and differentiation of cortical and striatal neurons [50,56].…”

Section: Introductionmentioning

confidence: 99%

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

2007

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Dopamine levels in the fetal brain were increased by administering the dopamine precursor 3,4-dihydroxy-L-phenylalanine (L-DOPA) to pregnant mice in drinking water. The L-DOPA exposure decreased bromodeoxyuridine (BrdU) labeling in the lateral ganglionic eminence and frontal cortical neuroepithelium but not medial or caudal ganglionic eminences. The regional differences appear to reflect heterogeneity in precursor cells' responses to dopamine receptor activation. Relative numbers of E15 generated neurons were decreased at postnatal day 21 (P21) in the caudate-putamen, nucleus accumbens and frontal cortex but not globus pallidus in the L-DOPA group. TUNEL labeling did not show significant differences on P0, P7 or P14 in the caudate-putamen or frontal cortex, suggesting that cell death was not altered. Although virtually all cells in the P21 brains that were labeled with the E15 BrdU injection were NeuN-positive, stereological analyses showed no significant changes in total numbers of NeuN-positive or NeuN-negative cells in the P21 caudate-putamen or frontal cortex. Thus persisting deficits in neuronal numbers were evident in the L-DOPA group only by birth-dating analyses and not upon gross histological examination of brain sections or analysis of total numbers of neurons or glia. One explanation for this apparent discrepancy is that L-DOPA exposure decreased cell proliferation at E15 but not at E13. By E15, expansion of the neuroepithelial precursor pool is complete and any decrease in cell proliferation likely produces only marginal decreases in the total numbers of cells generated. Our L-DOPA exposure model may be pertinent to investigations of neurological dysfunction produced by developmental dopamine imbalance.

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Dopamine Receptor Activation Modulates GABA Neuron Migration from the Basal Forebrain to the Cerebral Cortex

Cited by 120 publications

References 59 publications

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

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Dopamine Receptor Activation Modulates GABA Neuron Migration from the Basal Forebrain to the Cerebral Cortex

Cited by 120 publications

References 59 publications

Dopamine D2Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D2Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

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Product

Resources

About

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae