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Regional brain metabolism in a murine systemic lupus erythematosus model.

Vo A, Volpe BT, Tang CC, Schiffer WK, Kowal C, Huerta PT, Uluğ AM, Dewey SL, Eidelberg D, Diamond B - J. Cereb. Blood Flow Metab. (2014)

Bottom Line: We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis.Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach.These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb+ mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb+ mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb- mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb+ animals with hippocampal BBB breach and altered fear conditioning in DNRAb+ mice with amygdala BBB breach. In DNRAb+ mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb- mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

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Panel A shows the number of neurons in the ventral subiculum in the DNRAb+ mice was decreased (P<0.005) 4 weeks after bloor–brain barrier breach with lipopolysaccharide (LPS). This anatomic locus is comparable with the microPET loci. Neuron number in the hippocampal CA1, CA3 and entorhinal region was decreased in DNRAb+ mice. Notably, the number of neurons in the amygdala (lateral amygdala (LAd) and superior basolateral amygdala) was comparable. Neuron number was measured from both hemispheres of three animals measured at 4 weeks for each group. Box-and-Whisker plots display the median and 25th and 75th percentiles of the neuron number of animals in both groups. DNRAb+ mice had significant loss of neurons in the dorsal CA1 (P<0.0001), CA3 (P<0.008), ventral subiculum (P<0.005), and posterior entorhinal cortex (P<0.005; Mann–Whitney). Neuron number in the amygdala was comparable (P=1). (B) In DNRAb+ mice (red), there was a significant inverse correlation (P<0.02) between the neuron number in the ventral subiculum and metabolism, suggesting a compensatory response of the neurons or glial cells to the DRNAb-mediated insult. In contrast, the DNRAb− mice (black) demonstrate a positive correlation (P<0.02) between neuron number in the ventral subiculum and metabolism.
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fig2: Panel A shows the number of neurons in the ventral subiculum in the DNRAb+ mice was decreased (P<0.005) 4 weeks after bloor–brain barrier breach with lipopolysaccharide (LPS). This anatomic locus is comparable with the microPET loci. Neuron number in the hippocampal CA1, CA3 and entorhinal region was decreased in DNRAb+ mice. Notably, the number of neurons in the amygdala (lateral amygdala (LAd) and superior basolateral amygdala) was comparable. Neuron number was measured from both hemispheres of three animals measured at 4 weeks for each group. Box-and-Whisker plots display the median and 25th and 75th percentiles of the neuron number of animals in both groups. DNRAb+ mice had significant loss of neurons in the dorsal CA1 (P<0.0001), CA3 (P<0.008), ventral subiculum (P<0.005), and posterior entorhinal cortex (P<0.005; Mann–Whitney). Neuron number in the amygdala was comparable (P=1). (B) In DNRAb+ mice (red), there was a significant inverse correlation (P<0.02) between the neuron number in the ventral subiculum and metabolism, suggesting a compensatory response of the neurons or glial cells to the DRNAb-mediated insult. In contrast, the DNRAb− mice (black) demonstrate a positive correlation (P<0.02) between neuron number in the ventral subiculum and metabolism.

Mentions: Histopathological analysis with unbiased stereology was obtained in the dorsal CA1 and CA3 fields of the hippocampus, ventral subiculum, posterior entorhinal cortex, and the lateral anterior dorsal and superior basal lateral amygdala. DNRAb+ mice (N=3) displayed significant reductions in the number of neurons in the hippocampal regions previously shown to sustain neuron loss (the CA1, and also in the CA3, ventral subiculum and posterior entorhinal cortex) in comparison with DNRAb− mice (N=3). Importantly, neuron number was also depressed in the ventral subiculum, a region that overlapped with the microPET data. Neuron number in the amygdala was comparable (P=1) (Figure 2A). Correlations between cell number in the ventral subiculum and the metabolic activity in the corresponding regional cluster at 4 weeks post LPS (Figure 2B) differed for DNRAb+ and DNRAb− animals. DNRAb− mice exhibited a significant positive correlation between neuron number and metabolic activity (Figure 2B, open circles), contrasting with a negative correlation between neuron number and metabolic activity in this region in DNRAb+ mice (Figure 2B, green).


Regional brain metabolism in a murine systemic lupus erythematosus model.

Vo A, Volpe BT, Tang CC, Schiffer WK, Kowal C, Huerta PT, Uluğ AM, Dewey SL, Eidelberg D, Diamond B - J. Cereb. Blood Flow Metab. (2014)

Panel A shows the number of neurons in the ventral subiculum in the DNRAb+ mice was decreased (P<0.005) 4 weeks after bloor–brain barrier breach with lipopolysaccharide (LPS). This anatomic locus is comparable with the microPET loci. Neuron number in the hippocampal CA1, CA3 and entorhinal region was decreased in DNRAb+ mice. Notably, the number of neurons in the amygdala (lateral amygdala (LAd) and superior basolateral amygdala) was comparable. Neuron number was measured from both hemispheres of three animals measured at 4 weeks for each group. Box-and-Whisker plots display the median and 25th and 75th percentiles of the neuron number of animals in both groups. DNRAb+ mice had significant loss of neurons in the dorsal CA1 (P<0.0001), CA3 (P<0.008), ventral subiculum (P<0.005), and posterior entorhinal cortex (P<0.005; Mann–Whitney). Neuron number in the amygdala was comparable (P=1). (B) In DNRAb+ mice (red), there was a significant inverse correlation (P<0.02) between the neuron number in the ventral subiculum and metabolism, suggesting a compensatory response of the neurons or glial cells to the DRNAb-mediated insult. In contrast, the DNRAb− mice (black) demonstrate a positive correlation (P<0.02) between neuron number in the ventral subiculum and metabolism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126091&req=5

fig2: Panel A shows the number of neurons in the ventral subiculum in the DNRAb+ mice was decreased (P<0.005) 4 weeks after bloor–brain barrier breach with lipopolysaccharide (LPS). This anatomic locus is comparable with the microPET loci. Neuron number in the hippocampal CA1, CA3 and entorhinal region was decreased in DNRAb+ mice. Notably, the number of neurons in the amygdala (lateral amygdala (LAd) and superior basolateral amygdala) was comparable. Neuron number was measured from both hemispheres of three animals measured at 4 weeks for each group. Box-and-Whisker plots display the median and 25th and 75th percentiles of the neuron number of animals in both groups. DNRAb+ mice had significant loss of neurons in the dorsal CA1 (P<0.0001), CA3 (P<0.008), ventral subiculum (P<0.005), and posterior entorhinal cortex (P<0.005; Mann–Whitney). Neuron number in the amygdala was comparable (P=1). (B) In DNRAb+ mice (red), there was a significant inverse correlation (P<0.02) between the neuron number in the ventral subiculum and metabolism, suggesting a compensatory response of the neurons or glial cells to the DRNAb-mediated insult. In contrast, the DNRAb− mice (black) demonstrate a positive correlation (P<0.02) between neuron number in the ventral subiculum and metabolism.
Mentions: Histopathological analysis with unbiased stereology was obtained in the dorsal CA1 and CA3 fields of the hippocampus, ventral subiculum, posterior entorhinal cortex, and the lateral anterior dorsal and superior basal lateral amygdala. DNRAb+ mice (N=3) displayed significant reductions in the number of neurons in the hippocampal regions previously shown to sustain neuron loss (the CA1, and also in the CA3, ventral subiculum and posterior entorhinal cortex) in comparison with DNRAb− mice (N=3). Importantly, neuron number was also depressed in the ventral subiculum, a region that overlapped with the microPET data. Neuron number in the amygdala was comparable (P=1) (Figure 2A). Correlations between cell number in the ventral subiculum and the metabolic activity in the corresponding regional cluster at 4 weeks post LPS (Figure 2B) differed for DNRAb+ and DNRAb− animals. DNRAb− mice exhibited a significant positive correlation between neuron number and metabolic activity (Figure 2B, open circles), contrasting with a negative correlation between neuron number and metabolic activity in this region in DNRAb+ mice (Figure 2B, green).

Bottom Line: We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis.Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach.These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb+ mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb+ mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb- mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb+ animals with hippocampal BBB breach and altered fear conditioning in DNRAb+ mice with amygdala BBB breach. In DNRAb+ mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb- mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

Show MeSH
Related in: MedlinePlus