Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme

Siuciak, Judith A.; McCarthy, Sheryl A.; Chapin, Douglas S.; Martin, A.

doi:10.1007/s00213-007-1014-6

Cited by 103 publications

(79 citation statements)

References 75 publications

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“…Using mice deficient in PDE4B, it has been demonstrated that this subtype plays a critical role in lipopolysaccharide-induced signaling and inflammatory responses (Ariga et al, 2004;Jin et al, 2005a). Most recently, it has been shown that PDE4B is required for the antipsychotic effect of rolipram (Siuciak et al, 2007), which is consistent with the association of this subtype with schizophrenia (Millar et al, 2005). Nevertheless, little is known about the CNS function of PDE4B.…”

Section: Discussionmentioning

confidence: 82%

“…While the roles of these variants are still not known, recent studies using mice deficient in PDE4B have shown that this subfamily plays a complementary role in the control of neutrophil function (Ariga et al, 2004) and is required for antipsychotic effects of rolipram (Siuciak et al, 2007). In addition, PDE4B also is involved in schizophrenia by interacting with the DISC1 gene, a candidate susceptibility factor for schizophrenia (Clapcote et al, 2007;Millar et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

157

143

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Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression-and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4BÀ/À). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4BÀ/À mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4BÀ/À mice. Compared to PDE4B + / + littermates, PDE4BÀ/À mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4BÀ/À mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4BÀ/À mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4BÀ/À mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

157

143

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“…First, it is not unanimously accepted that amphetamineinduced hyperactivity is a valid model of manic behavior. Second, there is evidence that rolipram (discussed above) also decreases methamphetamineinduced hyperlocomotion (Siuciak et al, 2007).…”

Section: Glycogen Synthase Kinase-3 (Bipolar Disorder and Major Deprementioning

confidence: 99%

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Mathew

Manji

Charney

2008

Neuropsychopharmacol

207

140

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Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.

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“…PDE4 has been implicated as a player in the pathophysiology of schizophrenia and mood disorders through linkage studies as well as through its interaction with the schizophrenia candidate gene disrupted in schizophrenia 1 (DISC1) (12)(13). Genetic deletion of PDE4 isoforms in mice affects cognitive, depressive-related, and anxiety-related behaviors (14)(15)(16). Furthermore, PDE4 inhibitors improve sensorimotor gating, strengthen memory, and reduce depressive-related behaviors in rodents (e.g., [17][18][19][20][21][22][23].…”

Section: Pde11a Ko Mice Show a Subset Of Phenotypes Associated Withmentioning

confidence: 99%

“…If PDE11A is expressed only in a subpopulation of cells within a discrete subregion of the brain, one might not expect to detect expression when analyzing samples prepared from an entire brain (region). Evidence implicating other PDE families in brain function and psychiatric disease (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), along with a recent report linking PDE11A to major depressive disorder and antidepressant response (31), suggest that it is important to understand the role of PDE11A in the brain. Using in situ hybridization, quantitative real-time PCR, and Western blot, we clarify here where in the brain PDE11A is expressed and, by using PDE11A-deleted mice, we demonstrate a role for PDE11A in brain function.…”

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confidence: 99%

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly

Logue

Brennan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

156

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Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A −/− knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a twoto threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatricdisease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate α-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (γ2) and γ8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

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Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme

Cited by 103 publications

References 75 publications

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

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