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Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

View Article: PubMed Central - PubMed

ABSTRACT

Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder.

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The medial prelimbic cortex has deficits in PNNs that emerge during early adulthood (PND90).Panels show DAPI (a), PV+ cells (b), PNNs ((c); stained with WFA) from representative rats at PND90. Across both conditions the total number of DAPI labelled nuclei decreased from PND7 to PND21 before plateauing (main effect of Age, p < 0.0001). PV cell density increased from PND7 to PND35 before declining at PND90 (main effect of Age, p < 0.0001). PNN density increased throughout postnatal development with the greatest increases occurring from PND7 to 21, and PND35 to 90 (main effect of Age, p < 0.0001; Age × Treatment, p < 0.0001; Treatment, p < 0.05). In the PND90 cohort, a significant deficit in PNN density emerged in polyI:C treated animals as compared to saline-treated (p < 0.0001). There was also a significant reduction in the number of PV cells ensheathed in a PNN (main effect of Age, p < 0.0001; Treatment, p < 0.001). Insets are representative images from each condition. Scale bar represents 250 μm. *p<0.001.
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f2: The medial prelimbic cortex has deficits in PNNs that emerge during early adulthood (PND90).Panels show DAPI (a), PV+ cells (b), PNNs ((c); stained with WFA) from representative rats at PND90. Across both conditions the total number of DAPI labelled nuclei decreased from PND7 to PND21 before plateauing (main effect of Age, p < 0.0001). PV cell density increased from PND7 to PND35 before declining at PND90 (main effect of Age, p < 0.0001). PNN density increased throughout postnatal development with the greatest increases occurring from PND7 to 21, and PND35 to 90 (main effect of Age, p < 0.0001; Age × Treatment, p < 0.0001; Treatment, p < 0.05). In the PND90 cohort, a significant deficit in PNN density emerged in polyI:C treated animals as compared to saline-treated (p < 0.0001). There was also a significant reduction in the number of PV cells ensheathed in a PNN (main effect of Age, p < 0.0001; Treatment, p < 0.001). Insets are representative images from each condition. Scale bar represents 250 μm. *p<0.001.

Mentions: Representative immunofluorescent images from medial prelimbic cortex from an animal at PND 90 are illustrated in Fig. 2 (a–c show DAPI, PV, and WFA labeling, respectively, d shows a merged image). Consistent with previous research in human post-mortem tissue, PNNs were absent in infancy and increased throughout postnatal development in the prefrontal cortex30 (Fig. 2g). A two-way ANOVA revealed a significant overall effect of age on PNN density, (F(3,47) = 479.10, p < 0.0001), a significant main effect of prenatal treatment with PolyI:C (F(1,47) = 4.12, p < 0.05) and a significant interaction between treatment and age (F(3,47) = 11.20, p < 0.001). Post-hoc comparisons revealed a significant decrease in PNN density within the medial prelimbic cortex of polyI:C treated offspring relative to offspring from saline-treated dams at PND90 [SAL (M = 0.60 ± 0.03) vs. POL (M = 0.49 ± 0.01), t = 5.84, p < 0.0001]. As PNNs are closely associated with PV interneurons, we next evaluated PV cell density within the same region (Fig. 2f). A two-way ANOVA on PV neuron density revealed a significant overall effect of age, (F(3,47) = 56.59, p < 0.0001) but no significant main effect of treatment or age X treatment interaction. An analysis of the percentage of PV cells ensheathed by PNNs revealed a significant main effect of age (Fig. 2h) (F(3,47) = 203.3, p < 0.0001) and a significant interaction between treatment and age (F(3,47) = 6.36, p < 0.01). Post-hoc comparisons revealed a significant reduction in the percentage of PV cells surrounded by a PNN in polyI:C treated animals in the PND90 cohort relative to saline controls [SAL (M = 56.62 ± 3.72) vs. POL (M = 44.54 ± 0.70), t = 4.12, p < 0.001]. A two-way ANOVA on overall (DAPI+) cell density in prelimbic cortex revealed a significant effect of age (Fig. 2e) (F(3,47) = 31.28, p < 0.0001) but no significant effect of polyI:C treatment or interaction between treatment and age.


Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation
The medial prelimbic cortex has deficits in PNNs that emerge during early adulthood (PND90).Panels show DAPI (a), PV+ cells (b), PNNs ((c); stained with WFA) from representative rats at PND90. Across both conditions the total number of DAPI labelled nuclei decreased from PND7 to PND21 before plateauing (main effect of Age, p < 0.0001). PV cell density increased from PND7 to PND35 before declining at PND90 (main effect of Age, p < 0.0001). PNN density increased throughout postnatal development with the greatest increases occurring from PND7 to 21, and PND35 to 90 (main effect of Age, p < 0.0001; Age × Treatment, p < 0.0001; Treatment, p < 0.05). In the PND90 cohort, a significant deficit in PNN density emerged in polyI:C treated animals as compared to saline-treated (p < 0.0001). There was also a significant reduction in the number of PV cells ensheathed in a PNN (main effect of Age, p < 0.0001; Treatment, p < 0.001). Insets are representative images from each condition. Scale bar represents 250 μm. *p<0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120325&req=5

f2: The medial prelimbic cortex has deficits in PNNs that emerge during early adulthood (PND90).Panels show DAPI (a), PV+ cells (b), PNNs ((c); stained with WFA) from representative rats at PND90. Across both conditions the total number of DAPI labelled nuclei decreased from PND7 to PND21 before plateauing (main effect of Age, p < 0.0001). PV cell density increased from PND7 to PND35 before declining at PND90 (main effect of Age, p < 0.0001). PNN density increased throughout postnatal development with the greatest increases occurring from PND7 to 21, and PND35 to 90 (main effect of Age, p < 0.0001; Age × Treatment, p < 0.0001; Treatment, p < 0.05). In the PND90 cohort, a significant deficit in PNN density emerged in polyI:C treated animals as compared to saline-treated (p < 0.0001). There was also a significant reduction in the number of PV cells ensheathed in a PNN (main effect of Age, p < 0.0001; Treatment, p < 0.001). Insets are representative images from each condition. Scale bar represents 250 μm. *p<0.001.
Mentions: Representative immunofluorescent images from medial prelimbic cortex from an animal at PND 90 are illustrated in Fig. 2 (a–c show DAPI, PV, and WFA labeling, respectively, d shows a merged image). Consistent with previous research in human post-mortem tissue, PNNs were absent in infancy and increased throughout postnatal development in the prefrontal cortex30 (Fig. 2g). A two-way ANOVA revealed a significant overall effect of age on PNN density, (F(3,47) = 479.10, p < 0.0001), a significant main effect of prenatal treatment with PolyI:C (F(1,47) = 4.12, p < 0.05) and a significant interaction between treatment and age (F(3,47) = 11.20, p < 0.001). Post-hoc comparisons revealed a significant decrease in PNN density within the medial prelimbic cortex of polyI:C treated offspring relative to offspring from saline-treated dams at PND90 [SAL (M = 0.60 ± 0.03) vs. POL (M = 0.49 ± 0.01), t = 5.84, p < 0.0001]. As PNNs are closely associated with PV interneurons, we next evaluated PV cell density within the same region (Fig. 2f). A two-way ANOVA on PV neuron density revealed a significant overall effect of age, (F(3,47) = 56.59, p < 0.0001) but no significant main effect of treatment or age X treatment interaction. An analysis of the percentage of PV cells ensheathed by PNNs revealed a significant main effect of age (Fig. 2h) (F(3,47) = 203.3, p < 0.0001) and a significant interaction between treatment and age (F(3,47) = 6.36, p < 0.01). Post-hoc comparisons revealed a significant reduction in the percentage of PV cells surrounded by a PNN in polyI:C treated animals in the PND90 cohort relative to saline controls [SAL (M = 56.62 ± 3.72) vs. POL (M = 44.54 ± 0.70), t = 4.12, p < 0.001]. A two-way ANOVA on overall (DAPI+) cell density in prelimbic cortex revealed a significant effect of age (Fig. 2e) (F(3,47) = 31.28, p < 0.0001) but no significant effect of polyI:C treatment or interaction between treatment and age.

View Article: PubMed Central - PubMed

ABSTRACT

Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder.

No MeSH data available.


Related in: MedlinePlus