Phosphodiesterase 10A Is Tethered to a Synaptic Signaling Complex in Striatum

Russwurm, Corina; Koesling, Doris; Russwurm, Michael

doi:10.1074/jbc.m114.595769

Cited by 40 publications

(40 citation statements)

References 53 publications

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“…However, even if this is not the case, PDE inhibition could still influence the overall signaling in a therapeutic direction. Currently, researchers are just beginning to unravel the precise subcellular localization and the role of functional compartmentalization in physiological and pathological conditions of the fronto-striatal circuits (e.g., PDE10A: Russwurm et al, 2015; Li et al, 2016b; MacMullen et al, 2016). Another important consideration is that, in general, PDE-I research involving fronto-striatal disorders is based on the classical view of basal ganglia direct and indirect pathway functioning.…”

Section: Resultsmentioning

confidence: 99%

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Heckman

Duinen

Bollen

et al. 2016

IJNPPY

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Background:The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson’s disease, Huntington’s disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette’s syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits.Methods:Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed.Results:Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits.Conclusion:Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits.

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Section: Resultsmentioning

confidence: 99%

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Heckman

Duinen

Bollen

et al. 2016

IJNPPY

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“…Future work will include pathway-specific characterization of PDE10A inhibitors. Other mechanisms, such as regulation of PDE10A activity by its GAFb domain, PDE10A localization through palmitoylation, and unknown regulation through binding partners of PDE10A (Charych et al, 2010;Jäger et al, 2012;Russwurm et al, 2015), are worth evaluating.…”

Section: Study Limitationsmentioning

confidence: 99%

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Suzuki

Harada

Suzuki

et al. 2016

Neuropsychopharmacol

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Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D 1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D 2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

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“…Dopamine is provided by M1-projecting mesencephalic neurons and supports learning-related plasticity by inducing learning-relevant genes, enhancing cortical excitability, strengthening motor representations and supporting the formation of long-term potentiation (LTP, for review see . With respect to the interaction analysis, DA also seems also to influence synapse formation by regulating actin fibre cross-linking via Actn2 (Hodges, Vilchez, Asmussen, Whitmore, and Horwitz, 2014) and the formation of the postsynaptic complex via Pde10a and Ppp2r2a (Russwurm, Koesling, and Russwurm, 2015). Within the smaller cluster, proteins are enriched that facilitate synapse-formation by regulation of fatty-acid uptake (Lpl; (Xian, Liu, Yu, Wang, Miao, Zhang, Yu, Ross, Karasinska, Hayden, Liu, and Chui, 2009), promoting actin filament assembly (Dgkb; (Kobayashi, Hozumi, Ito, Hosoya, Kondo, and Goto, 2007) and spinogenesis (Sdc2; (Hu and Hsueh, 2014).…”

Section: Discussionmentioning

confidence: 99%

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

Hertler

Buitrago

Luft

et al. 2016

Neurobiology of Learning and Memory

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Motor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that depends on changes in gene expression. Here, we investigate the temporal profile of these changes during motor memory formation in response to a skilled reaching task in rats. mRNA-levels were measured 1h, 7h and 24h after the end of a training session using microarray technique. To assure learning specificity, trained animals were compared to a control group. In response to motor learning, genes are sequentially regulated with high time-point specificity and a shift from initial suppression to later activation. The majority of regulated genes can be linked to learning-related plasticity. In the gene-expression cascade following motor learning, three different steps can be defined: (1) an initial suppression of genes influencing gene transcription. (2) Expression of genes that support translation of mRNA in defined compartments. (3) Expression of genes that immediately mediates plastic changes. Gene expression peaks after 24h -this is a much slower time-course when compared to hippocampusdependent learning, where peaks of gene-expression can be observed 6-12h after training ended. AbstractMotor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that depends on changes in gene expression. Here, we investigate the temporal profile of these changes during motor memory formation in response to a skilled reaching task in rats. mRNA-levels were measured 1h, 7h and 24h after the end of a training session using microarray technique. To assure learning specificity, trained animals were compared to a control group. In response to motor learning, genes are sequentially regulated with high time-point specificity and a shift from initial suppression to later activation. The majority of regulated genes can be linked to learning-related plasticity. In the gene-expression cascade following motor learning, three different steps can be defined: 1) an initial suppression of genes influencing gene transcription. 2) Expression of genes that support translation of mRNA in defined compartments. 3) Expression of genes that immediately mediates plastic changes. Gene expression peaks after 24 hours -this is a much slower time-course when compared to hippocampus-dependent learning, where peaks of geneexpression can be observed 6 to 12 hours after training ended.3

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Phosphodiesterase 10A Is Tethered to a Synaptic Signaling Complex in Striatum

Cited by 40 publications

References 53 publications

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

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