Putting Together The Pieces of Phosphodiesterase Distribution Patterns In The Brain: A Jigsaw Puzzle of Cyclic Nucleotide Regulation

Kelly, Michy P.

doi:10.1002/9781118836507.ch02

Cited by 22 publications

(24 citation statements)

References 27 publications

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“…(A) As previously reported (Kelly et al, 2010, 2014; Kelly, 2014, 2015), PDE11A mRNA is selectively expressed in CA1 (and possibly ventral CA2), subiculum, and the adjacent amygdalohippocampal area (not shown at this level), with a 3- to 10-fold enrichment in ventral (VHIPP) versus dorsal hippocampus (DHIPP). (B) As expected, PDE11A heterozygous (HT; n = 6 (3 females)) mice show a 50% reduction in ventral hippocampal (VHIPP) PDE11A mRNA expression relative to wild-type (WT) littermates ( n = 7 (4 females)), as measured by Q-PCR ( t (11) = 3.47, P = 0.005).…”

Section: Figmentioning

confidence: 56%

“…As previously described (Kelly et al, 2010; Kelly, 2014; Pathak et al, 2015), to mitigate non-specific effects related to transfer efficiencies, film exposures, etc. across gels, Western blot data on a given gel were normalized to a reference group (e.g., GH).…”

Section: Methodsmentioning

confidence: 99%

“…In cases of significant ANOVAs, post hoc analyses were conducted using the Student–Newman–Keuls Method. As previously described (Kelly et al, 2008, 2010; Kelly, 2014; Pathak et al, 2015), statistical outliers >2 standard deviations from the mean were removed from analyses (outliers/total data points: Fig. 1C Left, 2/62; Fig.…”

Section: Methodsmentioning

confidence: 99%

“…1A) (Kelly et al, 2010, 2014; Kelly, 2014, 2015; Hegde et al, 2016; Pathak et al, in press) and little to no expression in peripheral organs (c.f., (Kelly, 2015)). PDE11A has been genetically and/or functionally associated with clinical phenotypes related to changes in social function, including major depressive disorder (Wong et al, 2006; Cabanero et al, 2009; Luo et al, 2009), suicide risk (an inactivating mutation, (Coon et al, 2013)), and lithium responsivity (Couzin, 2008; Kelsoe, 2010; Mertens et al, 2015; Pathak et al, in press).…”

Section: Introductionmentioning

confidence: 99%

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PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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Despite the fact that appropriate social behaviors are vital to thriving in one’s environment, little is understood of the molecular mechanisms controlling social behaviors or how social experience sculpts these signaling pathways. Here, we determine if Phosphodiesterase 11A (PDE11A), an enzyme that is restricted to the ventral hippocampal formation (VHIPP) and that breaks down cAMP and cGMP, regulates social behaviors. PDE11 wild-type (WT), heterozygous (HT), and knockout (KO) mice were tested in various social approach assays and gene expression differences were measured by RNA sequencing. The effect of social isolation on PDE11A4 compartmentalization and subsequent social interactions and social memory was also assessed. Deletion of PDE11A triggered age- and sex-dependent deficits in social approach in specific social contexts but not others. Mice appear to detect altered social behaviors of PDE11A KO mice, because C57BL/6J mice prefer to spend time with a sex-matched PDE11A WT vs. its KO littermate; whereas, a PDE11A KO prefers to spend time with a novel PDE11A KO vs. its WT littermate. Not only is PDE11A required for intact social interactions, we found that 1 month of social isolation vs. group housing decreased PDE11A4 protein expression specifically within the membrane fraction of VHIPP. This isolation-induced decrease in PDE11A4 expression appears functional because social isolation impairs subsequent social approach behavior and social memory in a PDE11A genotype-dependent manner. Pathway analyses following RNA sequencing suggests PDE11A is a key regulator of the oxytocin pathway and membrane signaling, consistent with its pivotal role in regulating social behavior.

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Section: Figmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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“…As previously described [6, 41, 42], to mitigate non-specific effects related to transfer efficiencies, film exposures, etc. across gels, Western blot data on a given gel were normalized to a reference group (e.g., WT).…”

Section: Methodsmentioning

confidence: 99%

PDE11A negatively regulates lithium responsivity

et al. 2016

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Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in IPSC-derived hippocampal neurons originating from lithium responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cAMP and cGMP. Here, we determined if decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus (DHIPP) and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding SNP at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a KO mice given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to WT littermates in tail suspension, an antidepressant predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine IL-6 relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant.

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Current Understanding of PDE10A in the Modulation of Basal Ganglia Circuitry

Schülke

Brandon²

2017

Advances in Neurobiology

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The basal ganglia are a forebrain network of interconnected nuclei that are involved in action selection, reward circuits and coordinating movement. PDE10A inhibition has been proposed as a novel way to modulate basal ganglia circuitry and to ameliorate symptoms in Huntington's disease, Parkinson's disease and Schizophrenia. However, despite encouraging results from pre-clinical models, PDE10A inhibitors failed to show efficacy as an antipsychotic in several clinical trials. PDE10A is expressed in the medium spiny neurons of the striatum and works to limit cyclic nucleotide signaling in response to modulatory neurotransmitters like dopamine. In this chapter, we will review the current literature on PDE10A and discuss how inhibition of PDE10A will result in alterations of the basal ganglia circuitry at the biochemical, physiological and behavioral level.

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Putting Together The Pieces of Phosphodiesterase Distribution Patterns In The Brain: A Jigsaw Puzzle of Cyclic Nucleotide Regulation

Cited by 22 publications

References 27 publications

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

PDE11A negatively regulates lithium responsivity

Current Understanding of PDE10A in the Modulation of Basal Ganglia Circuitry

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