Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations

Heckman, Pim R. A.; Blokland, Arjan; Bollen, Eva; Prickaerts, Jos

doi:10.1016/j.neubiorev.2018.02.007

Cited by 56 publications

(53 citation statements)

References 266 publications

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“…Stimulation of D2 receptors inhibits cyclic adenosine monophosphate (cAMP) production, while phosphodiesterase inhibitors have an opposing effect by preventing cAMP breakdown. Phosphodiesterase inhibitors may therefore have the potential to block the downstream effects of excessive D2 signalling, and also the potential benefit of boosting cortical D1 signalling. Although clinical trials testing these compounds have not yet been successful, there is a significant variability in the regional expression of phosphodiesterase inhibitor subtypes, and those showing the greatest cortical expression remain to be tested.…”

Section: Treatmentmentioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

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Section: Treatmentmentioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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“…The most important posttranscriptional modification is the phosphorylation of the amino acid residue Ser133 in the KID domain (Guo et al, 2017). This domain contains multiple phosphorylation sites for many canonical signaling pathways, such as Ras/Raf/MAPK/p90RSK, Ca 2+ /CaMK, PI3K/Akt/GSK3β, and cAMP/PKA pathways (Tang et al, 2014; Cheng et al, 2016; Xi et al, 2016; Zeng et al, 2016; Heckman et al, 2018), which, upon activation, lead to CREB’s antagonistic effects ( Figure 1 ).…”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

“…It is well documented that cAMP, through PKA, stimulates the phosphorylation of CREB at Ser133 and causes the activation of CREB (Herold et al, 2011; Heckman et al, 2018), while cGMP activates the downstream protein cGMP-dependent protein kinase G (PKG), which also phosphorylates the transcription factor CREB at Ser133 (Lueptow et al, 2016). This dual phosphorylation by PKA and PKG may amplify the CREB activity (Lu et al, 1999).…”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Wang

Lazarovici

et al. 2018

Front. Mol. Neurosci.

296

204

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Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal transduction is hyperactive. The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons. Dopamine affects the phosphorylation of CREB via G protein-coupled receptors. Neurotrophins, such as brain derived growth factor (BDNF), are critical regulators during neurodevelopment and synaptic plasticity. The CREB is one of the major regulators of neurotrophin responses since phosphorylated CREB binds to a specific sequence in the promoter of BDNF and regulates its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the brain of individuals suffering from schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. The CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and the pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression, and biological functions in the brain and its interaction with dopamine signaling, neurotrophins, and susceptibility genes for schizophrenia. Animal models in which CREB function is modulated, by either overexpression of the protein or knocked down through gene deletion/mutation, implicating CREB in schizophrenia and antipsychotic drugs efficacy are also discussed. Targeting research and drug development on CREB could potentially accelerate the development of novel medications against schizophrenia.

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“…PDEs are important negative regulators of PKA activity. Regulation of the striatal expression of PDEs has been reported in PD patients and animal models of PD, particularly a down-regulation of PDE4 and PDE10 (Heckman et al, 2018;Niccolini et al, 2015Niccolini et al, , 2017. Hence, we tested if PDE activity could be implicated in the cell type-specific upregulation of PKA activity observed after DA denervation.…”

Section: -Cell Type-specific Decrease In Pde Activity Contributes To mentioning

confidence: 96%

Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

Mariani

Longueville

Girault

et al. 2019

Neurobiology of Disease

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Parkinson's disease (PD) is characterized by severe locomotor deficits due to the disappearance of dopamine (DA) from the dorsal striatum. The development of PD symptoms and treatment-related complications such as dyskinesia have been proposed to result from complex alterations in intracellular signaling in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs, respectively) following loss of DA afferents. To identify cell-specific and dynamical modifications of signaling pathways associated with PD, we used a hemiparkinsonian mouse model with 6-hydroxydopamine (6-OHDA lesion) combined with twophoton fluorescence biosensors imaging in adult corticostriatal slices. After DA lesion, extracellular signal-regulated kinase (ERK) activation was found increased in response to DA D1 receptor (D1R) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 11 1 stimulation.The cAMP-dependent protein kinase (PKA) pathway contributing to ERK activation displayed supersensitive responses to D1R stimulation after 6-OHDA lesion. This cAMP/PKA supersensitivity was specific of D1R-responding SPNs and resulted from Gαolf upregulation and deficient phosphodiesterase activity. In lesioned striatum, the number of D1R-SPNs with spontaneous Ca 2+ transients augmented while Ca 2+ response to AMPA receptor stimulation specifically increased in iSPNs. Our work reveals distinct cell type-specific signaling alterations in the striatum after DA denervation. It suggests that over-activation of ERK pathway, observed in PD striatum, known to contribute to dyskinesia, may be linked to the combined dysregulation of DA and glutamate signaling pathways in the two populations of SPNs. These findings bring new insights into the implication of these respective neuronal populations in PD motor symptoms and the occurrence of PD treatment complications.

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Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations

Cited by 56 publications

References 266 publications

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

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