Maternal immune activation in neurodevelopmental disorders

Solek, Cynthia M.; Farooqi, Nasr; Verly, Myriam Maude; Lim, Tony K.Y.; Ruthazer, Edward S.

doi:10.1002/dvdy.24612

Cited by 126 publications

(104 citation statements)

References 298 publications

(383 reference statements)

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“…Acute disruption of the maternal environment during prenatal development can significantly contribute to risk for disorders such as autism spectrum disorder (ASD) and schizophrenia (Boksa, 2010;Hsiao and Patterson, 2011;Solek et al, 2018). For example, there is growing evidence that maternal infection during pregnancy is one of the most prominent environmental risk factors of neural developmental dysfunction in subsequent offspring (Basil et al, 2014;Bilbo et al, 2018;Garbett et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

Amodeo

Lai

Hassan

et al. 2019

Neurobiology of Disease

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Background: Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes. Methods: The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams. Results: Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations. Conclusions: These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.

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Section: Introductionmentioning

confidence: 99%

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

Amodeo

Lai

Hassan

et al. 2019

Neurobiology of Disease

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“…Prenatal inflammation and dysfunction of microglia, the brain resident macrophages, have both been associated with the etiology of several neuropsychiatric disorders, including schizophrenia (SZ) and autism spectrum disorders (ASD) (Beumer et al, 2012;Choi et al, 2016;Estes and McAllister, 2016;Hammond et al, 2018;Hanamsagar and Bilbo, 2017;Kim et al, 2017;Mattei et al, 2017;Patterson, 2011;Sekar et al, 2016;Shin Yim et al, 2017;Solek et al, 2018;Takano, 2015). However, how these prenatal immune challenges impact on the developmental trajectory of neocortical circuits remains to be fully examined.…”

Section: Introductionmentioning

confidence: 99%

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

Thion

Mosser

Férézou

et al. 2019

Preprint

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The etiology of neurodevelopmental disorders is linked to defects in Parvalbumin (PV)expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia, have a twostep impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a novel framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.

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“…Specifically, a bacterial infection during the second trimester of pregnancy or a viral infection in the first trimester have been correlated with the diagnosis of autism spectrum disorders (ASD) in children (Atladóttir et al 2010). To investigate the effects of in utero exposure of the fetus to a maternal immune activation (MIA), various animal models have been designed (Dean et al 2015;Giovanoli, Notter, et al 2015;Solek et al 2018;Bilbo et al 2018). Injection in pregnant rodents of cytokines (Smith et al 2007), bacterial cell wall endotoxin lipopolysaccharide (LPS) (Custódio et al 2018;Kirsten and Bernardi 2017), or the viral mimic double-stranded RNA polyinosinic-polycytidylic acid (Poly(I:C)) generate offspring with a variety of autistic-like behavioral impairments (Smith et al 2007;Meyer et al 2008;Hsiao and Patterson 2011).…”

Section: Introductionmentioning

confidence: 99%

The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

et al. 2018

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Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

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Maternal immune activation in neurodevelopmental disorders

Cited by 126 publications

References 298 publications

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

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