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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.


Nedd4-2 heterozygosis increases the response at low fEPSP stimulus intensity without affecting hippocampal basal synaptic transmission and Long-Term Potentiation (LTP).Extracellular recording in CA1 radiatum of field Excitatory Post Synaptic Potentials (fEPSP) obtained by stimulation of Schaffer collaterals. (A) Input/Output curve; initial slope of fEPSP obtained with increased stimulus intensity were plotted relative to the response normalized to the maximal response obtained (n = 18 per genotype). Note the statistically significant higher response at low stimulus intensity caused by NEDD4-2 reduction level. (B) Slope of fEPSP recorded in Wild-Type and NEDD4-2 +/− mice. Note that the LTP induced by high frequency stimulus is not statistically different between the 2 genotypes (n = 9 for each genotype). (C) Ratio of slope of paired fEPSP recorded at increasing interpulse time showing similar paired pulse facilitation between genotypes (n = 9 for each genotype).
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f4: Nedd4-2 heterozygosis increases the response at low fEPSP stimulus intensity without affecting hippocampal basal synaptic transmission and Long-Term Potentiation (LTP).Extracellular recording in CA1 radiatum of field Excitatory Post Synaptic Potentials (fEPSP) obtained by stimulation of Schaffer collaterals. (A) Input/Output curve; initial slope of fEPSP obtained with increased stimulus intensity were plotted relative to the response normalized to the maximal response obtained (n = 18 per genotype). Note the statistically significant higher response at low stimulus intensity caused by NEDD4-2 reduction level. (B) Slope of fEPSP recorded in Wild-Type and NEDD4-2 +/− mice. Note that the LTP induced by high frequency stimulus is not statistically different between the 2 genotypes (n = 9 for each genotype). (C) Ratio of slope of paired fEPSP recorded at increasing interpulse time showing similar paired pulse facilitation between genotypes (n = 9 for each genotype).

Mentions: To further characterize whether the Nedd4-2 haploinsufficiency may result in deficits that are not immediately apparent by behavioral or morphological characterization, we decided to analyze the basal synaptic transmission and LTP in these mice. LTP in the CA1 area of the dorsal hippocampus at 1 h after the conditioning in Nedd4-2+/− animals was similar to that found in WT mice, suggesting that loss of one copy of the gene does not affect this aspect of hippocampal synaptic plasticity (Fig. 4). However, Nedd4-2+/− mice had a significantly higher response at low stimulus intensity in the basal synaptic transmission, as assessed by the input–output curves (stimulus intensity vs. fEPSP slope) from the Schaffer collateral–CA1 region. These data suggest that in Nedd4-2 heterozygous mice, although LTP and presynaptic function are unaffected, there is a marginal increase in excitability of the Schaffer collateral -CA1 pathway (Fig. 4).


Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli
Nedd4-2 heterozygosis increases the response at low fEPSP stimulus intensity without affecting hippocampal basal synaptic transmission and Long-Term Potentiation (LTP).Extracellular recording in CA1 radiatum of field Excitatory Post Synaptic Potentials (fEPSP) obtained by stimulation of Schaffer collaterals. (A) Input/Output curve; initial slope of fEPSP obtained with increased stimulus intensity were plotted relative to the response normalized to the maximal response obtained (n = 18 per genotype). Note the statistically significant higher response at low stimulus intensity caused by NEDD4-2 reduction level. (B) Slope of fEPSP recorded in Wild-Type and NEDD4-2 +/− mice. Note that the LTP induced by high frequency stimulus is not statistically different between the 2 genotypes (n = 9 for each genotype). (C) Ratio of slope of paired fEPSP recorded at increasing interpulse time showing similar paired pulse facilitation between genotypes (n = 9 for each genotype).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Nedd4-2 heterozygosis increases the response at low fEPSP stimulus intensity without affecting hippocampal basal synaptic transmission and Long-Term Potentiation (LTP).Extracellular recording in CA1 radiatum of field Excitatory Post Synaptic Potentials (fEPSP) obtained by stimulation of Schaffer collaterals. (A) Input/Output curve; initial slope of fEPSP obtained with increased stimulus intensity were plotted relative to the response normalized to the maximal response obtained (n = 18 per genotype). Note the statistically significant higher response at low stimulus intensity caused by NEDD4-2 reduction level. (B) Slope of fEPSP recorded in Wild-Type and NEDD4-2 +/− mice. Note that the LTP induced by high frequency stimulus is not statistically different between the 2 genotypes (n = 9 for each genotype). (C) Ratio of slope of paired fEPSP recorded at increasing interpulse time showing similar paired pulse facilitation between genotypes (n = 9 for each genotype).
Mentions: To further characterize whether the Nedd4-2 haploinsufficiency may result in deficits that are not immediately apparent by behavioral or morphological characterization, we decided to analyze the basal synaptic transmission and LTP in these mice. LTP in the CA1 area of the dorsal hippocampus at 1 h after the conditioning in Nedd4-2+/− animals was similar to that found in WT mice, suggesting that loss of one copy of the gene does not affect this aspect of hippocampal synaptic plasticity (Fig. 4). However, Nedd4-2+/− mice had a significantly higher response at low stimulus intensity in the basal synaptic transmission, as assessed by the input–output curves (stimulus intensity vs. fEPSP slope) from the Schaffer collateral–CA1 region. These data suggest that in Nedd4-2 heterozygous mice, although LTP and presynaptic function are unaffected, there is a marginal increase in excitability of the Schaffer collateral -CA1 pathway (Fig. 4).

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.