Limits...
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.

No MeSH data available.


Related in: MedlinePlus

(a) Experimental timeline and setup. See Methods for details. (b) Dams receiving injections of polyI:C had significant weight loss compared to saline-injection dams over the 48 hours after injection (main effect of time, p < 0.0001; treatment, p < 0.05). (c) Regions of interest for our analysis. (d) Representative examples of PV cells (green), DAPI nuclei (blue) and PNNs, stained with wisteria floribunda agglutinin (WFA; purple), in the cortex. (e–h) An example high resolution image of a single PV cell surrounded by a PNN.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5120325&req=5

f1: (a) Experimental timeline and setup. See Methods for details. (b) Dams receiving injections of polyI:C had significant weight loss compared to saline-injection dams over the 48 hours after injection (main effect of time, p < 0.0001; treatment, p < 0.05). (c) Regions of interest for our analysis. (d) Representative examples of PV cells (green), DAPI nuclei (blue) and PNNs, stained with wisteria floribunda agglutinin (WFA; purple), in the cortex. (e–h) An example high resolution image of a single PV cell surrounded by a PNN.

Mentions: Dams received a single injection of either polyI:C or saline on GD15 consistent with protocols used previously10121314 (Fig. 1a). Administration of polyI:C to the pregnant dams induced a significant reduction in weight gain (Fig. 1b). Analysis of the weight of the dams (8, 24, and 48 h after injection) confirmed a significant main effect of time (F(2,30) = 98.52, p < 0.0001) and a significant main effect of treatment (F(1,15) = 5.30, p < 0.05; interaction p > 0.10). PolyI:C treatment did not affect maternal temperature (data not shown), consistent with previous studies from our group10121314. Average litter size (saline = 11.43 ± 0.6 pups/litter; polyI:C = 11.60 ± 1.2 pups/litter) and average pup weight at birth (saline = 7.04 ± 0.28 g/pup; polyI:C = 7.58 ± 0.27 pups/litter) were also not altered by treatment (statistics not shown).


Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation
(a) Experimental timeline and setup. See Methods for details. (b) Dams receiving injections of polyI:C had significant weight loss compared to saline-injection dams over the 48 hours after injection (main effect of time, p < 0.0001; treatment, p < 0.05). (c) Regions of interest for our analysis. (d) Representative examples of PV cells (green), DAPI nuclei (blue) and PNNs, stained with wisteria floribunda agglutinin (WFA; purple), in the cortex. (e–h) An example high resolution image of a single PV cell surrounded by a PNN.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120325&req=5

f1: (a) Experimental timeline and setup. See Methods for details. (b) Dams receiving injections of polyI:C had significant weight loss compared to saline-injection dams over the 48 hours after injection (main effect of time, p < 0.0001; treatment, p < 0.05). (c) Regions of interest for our analysis. (d) Representative examples of PV cells (green), DAPI nuclei (blue) and PNNs, stained with wisteria floribunda agglutinin (WFA; purple), in the cortex. (e–h) An example high resolution image of a single PV cell surrounded by a PNN.
Mentions: Dams received a single injection of either polyI:C or saline on GD15 consistent with protocols used previously10121314 (Fig. 1a). Administration of polyI:C to the pregnant dams induced a significant reduction in weight gain (Fig. 1b). Analysis of the weight of the dams (8, 24, and 48 h after injection) confirmed a significant main effect of time (F(2,30) = 98.52, p < 0.0001) and a significant main effect of treatment (F(1,15) = 5.30, p < 0.05; interaction p > 0.10). PolyI:C treatment did not affect maternal temperature (data not shown), consistent with previous studies from our group10121314. Average litter size (saline = 11.43 ± 0.6 pups/litter; polyI:C = 11.60 ± 1.2 pups/litter) and average pup weight at birth (saline = 7.04 ± 0.28 g/pup; polyI:C = 7.58 ± 0.27 pups/litter) were also not altered by treatment (statistics not shown).

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