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Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

View Article: PubMed Central - PubMed

ABSTRACT

Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities.

No MeSH data available.


Related in: MedlinePlus

Nedd4-2 heterozygous mice have increased locomotor activity.Animals were subjected to the open field (A–E) elevated plus maze (F,G), forced swim (H,I) and rota-rod (J) test. Histograms showing the results of the general behavioral characterization of Nedd4-2 heterozygous mice reveal increased exploratory behavior in the open field test (A–E). No changes in anxiety (F,G), depression (H,I), or muscle strength/co-ordination (J) were observed. Numbers of animals per group are indicated inside the histogram. N = 9–11. Results are expressed as the Mean ± SEM. *Indicates p < 0.05; Mann-Whitney test.
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f3: Nedd4-2 heterozygous mice have increased locomotor activity.Animals were subjected to the open field (A–E) elevated plus maze (F,G), forced swim (H,I) and rota-rod (J) test. Histograms showing the results of the general behavioral characterization of Nedd4-2 heterozygous mice reveal increased exploratory behavior in the open field test (A–E). No changes in anxiety (F,G), depression (H,I), or muscle strength/co-ordination (J) were observed. Numbers of animals per group are indicated inside the histogram. N = 9–11. Results are expressed as the Mean ± SEM. *Indicates p < 0.05; Mann-Whitney test.

Mentions: Since Nedd4-2 is highly expressed in the brain, to further evaluate its function on general physical and behavioral characteristics we subjected heterozygous mice to a battery of behavioral tests aimed at evaluating general locomotor activity, anxiety and/or depression-related behavior as well as muscle strength and coordination. Interestingly, we found that in the open field test, the total distance traveled by Nedd4-2 +/− mice was significantly higher compared to that of WT mice (Fig. 3A). This result was also confirmed by a concomitant reduced immobility time recorded for the mutant mice (Fig. 3B). We then evaluated these mice in the elevated plus maze test for assessment of anxiety related behavior. Although we found a tendency to an increase in the number of crosses between different arms of the maze and the time spent in the open arm for the Nedd4-2 +/− mice these data were not significant (Fig. 3F,G) suggesting that the increased activity of the Nedd4-2 mice in the open field test is not related to anxiety-related behavior. This conclusion is further supported by the similar number of ambulations, rearing and time spent in the center of the open field recorded for both genotypes (Fig. 3C–E). In addition, data from the forced-swim and rota rod test revealed no difference in depression-like behavior and muscle strength/coordination between the two groups of mice (Fig. 3H–J). Nevertheless, the significant alterations found in the open field analysis suggest that changes in Nedd4-2 levels can influence behavior.


Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli
Nedd4-2 heterozygous mice have increased locomotor activity.Animals were subjected to the open field (A–E) elevated plus maze (F,G), forced swim (H,I) and rota-rod (J) test. Histograms showing the results of the general behavioral characterization of Nedd4-2 heterozygous mice reveal increased exploratory behavior in the open field test (A–E). No changes in anxiety (F,G), depression (H,I), or muscle strength/co-ordination (J) were observed. Numbers of animals per group are indicated inside the histogram. N = 9–11. Results are expressed as the Mean ± SEM. *Indicates p < 0.05; Mann-Whitney test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015076&req=5

f3: Nedd4-2 heterozygous mice have increased locomotor activity.Animals were subjected to the open field (A–E) elevated plus maze (F,G), forced swim (H,I) and rota-rod (J) test. Histograms showing the results of the general behavioral characterization of Nedd4-2 heterozygous mice reveal increased exploratory behavior in the open field test (A–E). No changes in anxiety (F,G), depression (H,I), or muscle strength/co-ordination (J) were observed. Numbers of animals per group are indicated inside the histogram. N = 9–11. Results are expressed as the Mean ± SEM. *Indicates p < 0.05; Mann-Whitney test.
Mentions: Since Nedd4-2 is highly expressed in the brain, to further evaluate its function on general physical and behavioral characteristics we subjected heterozygous mice to a battery of behavioral tests aimed at evaluating general locomotor activity, anxiety and/or depression-related behavior as well as muscle strength and coordination. Interestingly, we found that in the open field test, the total distance traveled by Nedd4-2 +/− mice was significantly higher compared to that of WT mice (Fig. 3A). This result was also confirmed by a concomitant reduced immobility time recorded for the mutant mice (Fig. 3B). We then evaluated these mice in the elevated plus maze test for assessment of anxiety related behavior. Although we found a tendency to an increase in the number of crosses between different arms of the maze and the time spent in the open arm for the Nedd4-2 +/− mice these data were not significant (Fig. 3F,G) suggesting that the increased activity of the Nedd4-2 mice in the open field test is not related to anxiety-related behavior. This conclusion is further supported by the similar number of ambulations, rearing and time spent in the center of the open field recorded for both genotypes (Fig. 3C–E). In addition, data from the forced-swim and rota rod test revealed no difference in depression-like behavior and muscle strength/coordination between the two groups of mice (Fig. 3H–J). Nevertheless, the significant alterations found in the open field analysis suggest that changes in Nedd4-2 levels can influence behavior.

View Article: PubMed Central - PubMed

ABSTRACT

Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities.

No MeSH data available.


Related in: MedlinePlus