Increased white matter neuron density in a rat model of maternal immune activation — Implications for schizophrenia

Duchatel, Ryan J.; Jobling, Phillip; Graham, Brett A.; Harms, Lauren; Michie, Patricia T.; Hodgson, Deborah M.; Tooney, Paul A.

doi:10.1016/j.pnpbp.2015.09.006

Cited by 29 publications

(16 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Maternal immune activation (MIA) is arguably one of the most utilised animal models to investigate the biological mechanisms underlying neurodevelopmental brain disorders, inducing a systemic immune response in the pregnant dam and producing offspring with altered immune, behavioural, and neural phenotypes that are seen in numerous neuropsychiatric disorders [36-39]. If analogous GI abnormalities were also demonstrated in this model, it presents itself as a potential tool to investigate GBA deficits underlying neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

Hollins

Brock

Barreto

et al. 2018

Neuroimmunomodulation

View full text Add to dashboard Cite

Objectives: Gastrointestinal (GI) inflammation and GI integrity deficits are common comorbidities of neuropsychiatric disorders. Ongoing research suggests that these aberrations may be contributing to heightened immune signals that have the potential to disrupt neuronal homeostasis and exacerbate behavioural deficits. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the maternal immune activation (MIA) model, produced GI inflammation and integrity disruptions in association with anxiety-like behaviour. Methods: Pregnant Wistar rats were exposed to the viral mimetic polyriboinosinic:polyribocytidilic acid (polyI:C) on gestational days (GD) 10 and 19. Evidence of ANS activation, GI inflammation, and GI barrier integrity was assessed in both neonatal (postnatal day, P7) and adult (P84) offspring. Anxiety-like behaviour was assessed at P100. Results: Neonatal MIA offspring exhibited an altered intestinal inflammatory profile and evidence of an increase in lymphoid aggregates. MIA neonates also displayed disruptions to GI barrier tight junction protein mRNA. In addition, adult MIA offspring exhibited an increase in anxiety-like behaviours. Conclusion: These results indicate that the MIA rat model, which is well documented to produce behavioural, neurochemical, and neuroanatomical abnormalities, also produces GI inflammation and integrity disruptions. We suggest that this model may be a useful tool to elucidate biological pathways associated with neuropsychiatric disorders.

show abstract

Section: Introductionmentioning

confidence: 99%

A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

Hollins

Brock

Barreto

et al. 2018

Neuroimmunomodulation

View full text Add to dashboard Cite

show abstract

“…Our detection of reduced SST mRNA in the grey matter suggests MIA during either the initial development of the ganglionic eminence 54 , or the time of neuronal tangential migration 55,56 could alter the migration or survival of SST cortical interneurons. Interestingly, late gestation polyI:C offspring exhibit increased SST-positive IWMNs in more extensive regions of white matter compared to early gestation polyI:C offspring 86 . Given that SSTR2 is highly expressed on migrating neurons during early neurodevelopment in both rat and human 87 , our present findings may indicate a link between exaggerated IWMN pathology and SSTR2 deficits in late gestation polyI:C offspring.…”

Section: Discussionmentioning

confidence: 88%

“…Increased SST-positive interstitial white matter neurons (IWMN) and concurrent decreases in SST mRNA in the grey matter is reported in post-mortem frontal cortex from schizophrenia cases 24,85 . Recent studies show that both early gestation and late gestation polyI:C treatment increased the number of SST-positive IWMNs in regions that extend underneath the cingulate cortex in adult rat offspring 86 . Our detection of reduced SST mRNA in the grey matter suggests MIA during either the initial development of the ganglionic eminence 54 , or the time of neuronal tangential migration 55,56 could alter the migration or survival of SST cortical interneurons.…”

Section: Discussionmentioning

confidence: 99%

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats

Rahman

Weickert

Harms

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing. Neural activity between the cortex and striatum regulates motor, cognitive, and limbic function, and aspects of these modalities are perturbed in people with schizophrenia 1,2. This neural activity is influenced by local inhibitory neurons, and the dysregulation of inhibition is postulated as a central contributor in the development of schizophrenia. Inhibitory tone is mainly established during early neurodevelopment to coordinate efficient neurotransmission 3,4. Inhibitory interneurons migrate from the ganglionic eminence and the subventricular zone through the white matter to reach their destination in the cortical grey matter (see 5 for review) and hippocampus (see 6 for review). Striatal neurons are largely generated from the ganglionic eminences 7. Perturbations during this neurodevelopmental epoch is therefore postulated to dysregulate inhibitory tone in the brain 8 and contribute to the behavioural phenotypes in schizophrenia (see 9,10 for review). Glutamate decarboxylase-1 (GAD1) is one of the enzymes that catalyses the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA) 11. There are two main subsets of GABAergic neurons that are distinguished based on their expression of the calcium-binding protein, parvalbumin (PVALB), or the neuropeptide hormone, somatostatin (SST) (see 12 for review). Studies in post-mortem human brain show that schizophrenia cases have reduced cortical 13 , hippocampal 14,15 , and striatal 16,17 GABAergic indices that suggest that these regions may contribute to the cognitive deficits exhibited by people with schizophrenia. The most consistently reported inhibitory deficits in the cortex of people with s...

show abstract

“…71 Extremely premature birth is known to be associated with an elevated risk of development of ASD or schizophrenia (the relative risk ratios are 9.7 and 4.5, respectively), 72,73 as well as the development of other disabilities. 74,75 Increase in the number/densities of WM neurons was also reported in a rat model of experimental maternal immune activation (MIA) produced by injection of PolyI:C. 76 Since MIA is also implicated as one of the environmental risk factors for the development of ASD and schizophrenia, 77 these results together suggest that the increased densities/number of WM neurons might be associated with the environmental risk factors for neuropsychiatric disorders.…”

Section: Migration Failure Of the Neocortical Neuronsmentioning

confidence: 85%

Increased densities of white matter neurons as a cross‐disease feature of neuropsychiatric disorders

Kubo

2020

Psychiatry Clin Neurosci

View full text Add to dashboard Cite

While neurons of the human cerebral cortex are mainly distributed in the gray matter, the white matter (WM) also contains some excitatory and inhibitory neurons, so‐called WM neurons. Studies on the cytoarchitectural alterations in the brains of patients with neuropsychiatric disorders have repeatedly reported increased densities of the WM neurons in a proportion of patients with schizophrenia and autism spectrum disorder. Although some studies have demonstrated increased densities of superficial WM neurons, others have demonstrated increased densities of deep WM neurons and increased WM neuron densities can be considered as one of the cross‐disease features of neuropsychiatric disorders. Nevertheless, what actually causes the increase in the densities of the WM neurons still remains under debate, and several hypothetical mechanisms have been proposed. The WM neurons in normal brains are considered as remnants of the subplate neurons, which represent a transient cytoarchitectural zone present during development of the mammalian neocortex; it has been suggested that increased densities of the WM neurons could result from inappropriate apoptosis of the subplate neurons in the brains of patients with neuropsychiatric disorders. On the other hand, recent experimental studies have demonstrated that genetic and environmental factors that enhance the risk of development of neuropsychiatric disorders could cause altered distribution of neurons in the WM. To understand the pathophysiology underlying the increased densities of the WM neurons, it is important to investigate the cellular characteristics of the WM neurons in the brains of both normal subjects and patients with neuropsychiatric disorders.

show abstract

Increased white matter neuron density in a rat model of maternal immune activation — Implications for schizophrenia

Cited by 29 publications

References 64 publications

A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats

Increased densities of white matter neurons as a cross‐disease feature of neuropsychiatric disorders

Contact Info

Product

Resources

About