Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice

Hebb, Andrea L.O.; Robertson, Harold A.; Denovan‐Wright, Eileen M.

doi:10.1016/j.euroneuro.2007.08.002

Cited by 53 publications

(42 citation statements)

References 64 publications

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“…Finally, we also showed that PDE10A mRNA is increased in HPRT-deficient striatal cells. PDE10a is highly enriched in the striatum and is known to be important in regulating striatal cell signaling [43]–[45]. The demonstration in this study of increased gene expression of PDE10a in HPRT-deficient striatal cells is consistent with our recent demonstration of enhanced PDE10a expression and activity in HPRT-deficient neuronal cell lines [21].…”

Section: Discussionsupporting

confidence: 91%

Striatal Neurodevelopment Is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF/TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome

2014

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Lesch-Nyhan Syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This syndrome is characterized by an array of severe neurological impairments that in part originate from striatal dysfunctions. However, the molecular and cellular mechanisms underlying these dysfunctions remain largely unidentified. In this report, we demonstrate that HPRT-deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b). The data also reveal that the down-regulated expression of Bcl11b in HPRT-deficient immortalized mouse striatal (STHdh) neural stem cells is accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32, (DARPP-32). Furthermore, we demonstrate that components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation are markedly increased in HPRT-deficient cells and in the striatum of HPRT knockout mouse. Consequently, the HPRT-deficient cells display superior protection against reactive oxygen species (ROS)-mediated cell death upon exposure to hydrogen peroxide. These findings suggest that the purine metabolic defect caused by HPRT-deficiency, while it may provide neuroprotection to striatal neurons, affects key genes and signaling pathways that may underlie the neuropathogenesis of LNS.

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Section: Discussionsupporting

confidence: 91%

Striatal Neurodevelopment Is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF/TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome

2014

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“…A pathological hallmark of HD, neuronal intranuclear inclusions (NII) was first found in the R6 lines and has since been one of the most utilized histopathological markers in mouse models of HD as well as in humans (Becher, et al, 1998, Davies, et al, 1997, Gutekunst, et al, 1999, Morton, et al, 2000, Schilling, et al, 1999). Levels of striatally enriched transcripts, similar to that observed in humans, are also dysregulated in transgenic mice such as the R6 lines (Bibb, et al, 2000, Denovan-Wright and Robertson, 2000, Dowie, et al, 2009, Hebb, et al, 2004, Hebb, et al, 2008, Hu, et al, 2004, Kuhn, et al, 2007, Luthi-Carter, et al, 2000, McCaw, et al, 2004, van Dellen, et al, 2000)…”

Section: Introductionmentioning

confidence: 53%

Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats

Rising

Carlson

et al. 2011

Experimental Neurology

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The discovery of the gene mutation responsible for Huntington's Disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of the and enabled development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for the heterozygote, homozygote and their non-transgenic littermates and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to unaffected littermates, similarly to the cortical thinning recently reported in HD.

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“…After blocking (Roti-Block; Carl Roth), proteins were detected using the following antibodies: PDE10A, AKAP150, and NMDA⑀1 (see above), NMDA⑀2 (sc-1469, Santa Cruz), PP2B (sc-6123, Santa Cruz), and PSD95 (MA1-046, Thermo Scientific). AntipPDE10A was generated in rabbits against the phosphorylated N-terminal peptide (amino acids [11][12][13][14][15][16][17][18][19][20]. Purification of the antiserum was performed according to the manufacturer's instructions (PSL, Heidelberg, Germany).…”

Section: Methodsmentioning

confidence: 99%

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

Russwurm

Koesling

Russwurm

2015

Journal of Biological Chemistry

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Background:In striatum, cortical glutamatergic and midbrain dopaminergic inputs are integrated via cAMP. Results: PDE10A, the major cAMP-hydrolyzing enzyme in striatum, is targeted into a signaling complex containing the scaffolding proteins AKAP150, PSD95, and the NMDA receptor and released upon phosphorylation. Conclusion: Targeting of PDE10 is under control of cAMP/PKA activity. Significance: Phosphorylation-dependent release of PDE10 gives rise to a feed forward mechanism.

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Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice

Cited by 53 publications

References 64 publications

Striatal Neurodevelopment Is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF/TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome

Striatal Neurodevelopment Is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF/TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome

Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats

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

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