A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

Beaulieu, Jean‐Martin

doi:10.1503/jpn.110011

Cited by 214 publications

(170 citation statements)

References 129 publications

(185 reference statements)

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“…In general, a complex link between 5-HT2A and dopamine tone appears to modulate brain activity (Di Pietro and Seamans, 2007;Lieberman et al, 1998). Consistently, 5-HT2A and D2 receptors are both located on prefrontal pyramidal and nonpyramidal neurons (Fink and Gothert, 2007;Goldman-Rakic, 1998, 2000;Seamans and Yang, 2004), and their signaling is also transmitted through the common intraneuronal pathways (Beaulieu, 2012;de Bartolomeis et al, 2013). Overall, these findings suggest that the relationship between D2 and 5-HT2A modulates neuronal function through multiple mechanisms, and that their balanced stimulation is crucial.…”

Section: Introductionmentioning

confidence: 79%

“…Thus, genetically induced levels of 5-HT2A receptors may in turn interact with lower or greater expression of D2L postsynaptic receptors as a function of DRD2 variation in determining differential levels of stimulation of prefrontal pyramidal neurons or interneurons of relevance for cognitive processing. Another synergistic or alternative mechanism of the combined effect of rs1076560 and rs6314 on working memory processing is that stimulation of D2 and 5-HT2A receptors implicates intraneuronal adjustments that modulate common pathways including molecules such as AKT1 and GSK3beta (Beaulieu, 2012;de Bartolomeis et al, 2013), whose expression and related genetic variation have been associated with schizophrenia (Blasi et al, 2011(Blasi et al, , 2013bTan et al, 2008). In line with the relevance of common signaling cascades, current evidence also suggests that the cross-talk between D2 and 5-HT2A may be facilitated by the assembly of heteromers (Albizu et al, 2011;de Bartolomeis et al, 2013;Fuxe et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

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Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n ¼ 63 and n ¼ 54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.

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Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

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“…Many G-protein-coupled receptors, including 5HT-Rs and DA-Rs, regulate Ras-PI3K/PKB signaling (Mattingly and Macara 1996;Murga et al 1998;Neves et al 2002;Qin et al 2005;Beaulieu 2012). We show here that both 5HT and DA modulators can enhance the upstream input to the Ras-PI3K/PKB signaling pathway (e.g., via potentiating upstream NMDA-R activity) (see Bekkers 1993;Qin et al 2005) and thus partially rescue the impaired synaptic GluA1 delivery and learning deficits in Fmr1 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

et al. 2014

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Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT 2B -Rs) or dopamine (DA) subtype 1-like receptors (D 1 -Rs) and/or those inhibiting 5HT 2A -Rs or D 2 -Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDAapproved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

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“…Akt'ın, glikoz metabolizması, çeşitli genlerin transkripsiyonu, hücre proliferasyonu, anjiyogenez, apoptoz ve daha birçok fizyolojik sürece katkı-da bulunduğu bilinmektedir. Akt'ın katalitik olarak aktive edilebilmesi için fosfoinozitid-3 kinaz (PI3K) tarafından fosforilasyona uğratılması gerekir (13)(14)(15). Bazı G proteini ile kenetli reseptörler veya tirozin kinaz B (TrkB) reseptörlerinin uyarılması fosfoinozitol sinyal yolağı üzerinden PI3K aktivitesini arttırarak Akt'ın fosforilasyonu ve aktivasyonuyla sonuçlanır (11).…”

Section: Akt Ve Gsk-3 Yolağıunclassified

The involvement of Akt and GSK-3: Two pathways, two pathology

Şahin¹,

Ünal²,

Arıcıoğlu³

2014

MUSBED

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A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

Cited by 214 publications

References 129 publications

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

The involvement of Akt and GSK-3: Two pathways, two pathology

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