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Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

Bottom Line: Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs.Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.

Results: An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.

Conclusion: Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

No MeSH data available.


Related in: MedlinePlus

Ppar-α loss of function promotes an NMDA hypofunction-like condition. Non-competitive NMDAR antagonist–induced locomotion is diminished in Ppar-α −/− mice. (A) Time course of MK-801–induced locomotor activity (0.1 mg kg-1 subcutaneous; two way ANOVA repeated-measures; F(1,360) = 5.81, p = 0.0292; n = 7–11). (B) Time course of ketamine–induced locomotor activity (20 mg/kg−1, IP; two way ANOVA repeated-measures; F(1,348) = 6.29, p = 0.0275; n = 7–9). (C) Decreased cortical expression of parvalbumin (PV) interneurons in Ppar-α  mice; immunofluorescence (PV) staining in the prefrontal infralimbic cortex (top panel; scale bar 200 μm) and hippocampus (middle panel; scale bar 200 μm). Bottom panel – digital magnification of cortical PV interneurons (scale bar 50 μm). (D) Western blot of PV expression in frontal cortical and hippocampal explants. (E) Alterations of baseline cortical oscillations in awake behaving Ppar-α −/− mice. Average relative power in the alpha, beta (top) and gamma and theta (bottom) frequency bands are shown (n = 6 mice/genotype; **p = 0.0022, two-tailed Mann Whitney test).
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fig3: Ppar-α loss of function promotes an NMDA hypofunction-like condition. Non-competitive NMDAR antagonist–induced locomotion is diminished in Ppar-α −/− mice. (A) Time course of MK-801–induced locomotor activity (0.1 mg kg-1 subcutaneous; two way ANOVA repeated-measures; F(1,360) = 5.81, p = 0.0292; n = 7–11). (B) Time course of ketamine–induced locomotor activity (20 mg/kg−1, IP; two way ANOVA repeated-measures; F(1,348) = 6.29, p = 0.0275; n = 7–9). (C) Decreased cortical expression of parvalbumin (PV) interneurons in Ppar-α mice; immunofluorescence (PV) staining in the prefrontal infralimbic cortex (top panel; scale bar 200 μm) and hippocampus (middle panel; scale bar 200 μm). Bottom panel – digital magnification of cortical PV interneurons (scale bar 50 μm). (D) Western blot of PV expression in frontal cortical and hippocampal explants. (E) Alterations of baseline cortical oscillations in awake behaving Ppar-α −/− mice. Average relative power in the alpha, beta (top) and gamma and theta (bottom) frequency bands are shown (n = 6 mice/genotype; **p = 0.0022, two-tailed Mann Whitney test).

Mentions: We next investigated the response of Ppar-α −/− mice to a pharmacological model of NMDA hypofunction. Mice were challenged with vehicle or NMDA receptor antagonists that promote behavioral dysinhibition, MK-801 (0.1 mg kg−1, SC) or ketamine (20 mg kg−1, IP) [16]. Ppar-α −/− mice were hypo-responsive to the locomotor effects of both MK-801 (Figure 3A) and ketamine (Figure 3B) in the open field assay. Thus, these results reveal that mice lacking Ppar-α are resistant to the behavioral dysinhibitory effect of NMDA antagonists.


Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

Ppar-α loss of function promotes an NMDA hypofunction-like condition. Non-competitive NMDAR antagonist–induced locomotion is diminished in Ppar-α −/− mice. (A) Time course of MK-801–induced locomotor activity (0.1 mg kg-1 subcutaneous; two way ANOVA repeated-measures; F(1,360) = 5.81, p = 0.0292; n = 7–11). (B) Time course of ketamine–induced locomotor activity (20 mg/kg−1, IP; two way ANOVA repeated-measures; F(1,348) = 6.29, p = 0.0275; n = 7–9). (C) Decreased cortical expression of parvalbumin (PV) interneurons in Ppar-α  mice; immunofluorescence (PV) staining in the prefrontal infralimbic cortex (top panel; scale bar 200 μm) and hippocampus (middle panel; scale bar 200 μm). Bottom panel – digital magnification of cortical PV interneurons (scale bar 50 μm). (D) Western blot of PV expression in frontal cortical and hippocampal explants. (E) Alterations of baseline cortical oscillations in awake behaving Ppar-α −/− mice. Average relative power in the alpha, beta (top) and gamma and theta (bottom) frequency bands are shown (n = 6 mice/genotype; **p = 0.0022, two-tailed Mann Whitney test).
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fig3: Ppar-α loss of function promotes an NMDA hypofunction-like condition. Non-competitive NMDAR antagonist–induced locomotion is diminished in Ppar-α −/− mice. (A) Time course of MK-801–induced locomotor activity (0.1 mg kg-1 subcutaneous; two way ANOVA repeated-measures; F(1,360) = 5.81, p = 0.0292; n = 7–11). (B) Time course of ketamine–induced locomotor activity (20 mg/kg−1, IP; two way ANOVA repeated-measures; F(1,348) = 6.29, p = 0.0275; n = 7–9). (C) Decreased cortical expression of parvalbumin (PV) interneurons in Ppar-α mice; immunofluorescence (PV) staining in the prefrontal infralimbic cortex (top panel; scale bar 200 μm) and hippocampus (middle panel; scale bar 200 μm). Bottom panel – digital magnification of cortical PV interneurons (scale bar 50 μm). (D) Western blot of PV expression in frontal cortical and hippocampal explants. (E) Alterations of baseline cortical oscillations in awake behaving Ppar-α −/− mice. Average relative power in the alpha, beta (top) and gamma and theta (bottom) frequency bands are shown (n = 6 mice/genotype; **p = 0.0022, two-tailed Mann Whitney test).
Mentions: We next investigated the response of Ppar-α −/− mice to a pharmacological model of NMDA hypofunction. Mice were challenged with vehicle or NMDA receptor antagonists that promote behavioral dysinhibition, MK-801 (0.1 mg kg−1, SC) or ketamine (20 mg kg−1, IP) [16]. Ppar-α −/− mice were hypo-responsive to the locomotor effects of both MK-801 (Figure 3A) and ketamine (Figure 3B) in the open field assay. Thus, these results reveal that mice lacking Ppar-α are resistant to the behavioral dysinhibitory effect of NMDA antagonists.

Bottom Line: Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs.Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.

Results: An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.

Conclusion: Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

No MeSH data available.


Related in: MedlinePlus