Prenatal environmental stressors impair postnatal microglia function and adult behavior in males

Block, Carina L.; Eroglu, Oznur; Mague, Stephen D.; Smith, Caroline J.; Ceasrine, Alexis M; Sriworarat, Chaichontat; Blount, Cameron; Beben, Kathleen A.; Malacon, Karen; Ndubuizu, Nkemdilim; Talbot, Austin; Gallagher, Neil M.; Jo, Yong Suk; Nyangacha, Timothy; Carlson, David; Dzirasa, Kafui; Eroğlu, Çağla; Bilbo, Staci D.

doi:10.1016/j.celrep.2022.111161

Cited by 51 publications

(45 citation statements)

References 107 publications

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“…The postsynaptic and presynaptic puncta were analyzed as previously described ( Ippolito & Eroglu, 2010 ; Block et al, 2022 ). For each area of the brain, using both the 488-nm channel to detect SYN and the 555-nm channel to detect the PSD95, a z-stack for each SC section was collected in LAS X software for a total depth of 5 μm (15 × 0.33 μm optical sections) at 63× magnification using multiphoton laser scanning microscopy.…”

Section: Methodsmentioning

confidence: 99%

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

et al. 2022

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TSPAN7 is related to various neurological disorders including autism spectrum disorder (ASD). However, the underlying synaptic mechanism of TSPAN7 in ASD is still unclear. Here, we showed thatTspan7knockout rats exhibited ASD-like and ID-like behavioral phenotypes, brain structure alterations including decreased hippocampal and cortical volume, and related pathological changes including reduced hippocampal neurons number, neuronal complexity, dendritic spines, and synapse-associated proteins. Then, we found that TSPAN7 deletion interrupted the integrin β1/FAK/SRC signal pathway that was followed by the down-regulation of PSD95, SYN, and GluR1/2, which are key synaptic integrity-related proteins. Furthermore, reactivation of SRC restored the expression of synaptic integrity-related proteins in primary neurons of TSPAN7 knockout brains. Taken together, our results suggested that TSPAN7 knockout caused ASD-like and ID-like behaviors in rats and impaired neuronal synapses possibly through the down-regulation of the integrin β1/FAK/SRC signal pathway, which might be a new mechanism on regulation of synaptic proteins expression and on ASD pathogenesis by mutated TSPAN7. These findings provide novel insights into the role of TSPAN7 in psychiatric diseases and highlight integrin β1/FAK/SRC as a potential target for ASD therapy.

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Section: Methodsmentioning

confidence: 99%

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

et al. 2022

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“…They identified male-specific impairments in social behaviors that were linked to altered microglial pruning of developing thalamocortical synapses in the anterior cingulate cortex specifically in males. Inhibiting microglial phagocytosis within the anterior cingulate cortex during the critical developmental pruning window mimicked the pollution plus stress male phenotype, supporting the role of male-specific alterations in microglial function and behavioral impairments related to neurodevelopmental disorders (Block et al, 2022).…”

Section: Brain and Behavior Disordersmentioning

confidence: 69%

“…Gestational cold stress impaired adult social preference in both sexes but was rescued by gestational microglial depletion only in males, suggesting that the adult social deficits are driven by non-microglial mechanisms in females (Rosin et al, 2021 ). Recent work from Block et al ( 2022 ) combined prenatal air pollution exposure with postnatal maternal stress. They identified male-specific impairments in social behaviors that were linked to altered microglial pruning of developing thalamocortical synapses in the anterior cingulate cortex specifically in males.…”

Section: Brain and Behavior Disordersmentioning

confidence: 99%

Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior

Sullivan

Ciernia

2022

Front. Behav. Neurosci.

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Microglia are brain-resident immune cells that play a critical role in synaptic pruning and circuit fine-tuning during development. In the adult brain, microglia actively survey their local environment and mobilize inflammatory responses to signs of damage or infection. Sex differences in microglial gene expression and function across the lifespan have been identified, which play a key role in shaping brain function and behavior. The levels of sex hormones such as androgens, estrogens, and progesterone vary in an age-dependent and sex-dependent manner. Microglia respond both directly and indirectly to changes in hormone levels, altering transcriptional gene expression, morphology, and function. Of particular interest is the microglial function in brain regions that are highly sexually differentiated in development such as the amygdala as well as the pre-optic and ventromedial hypothalamic regions. With a focus on hormone-sensitive developmental windows, this review compares male and female microglia in the embryonic, developing, and adult brain with a particular interest in the influence of sex hormones on microglial wiring of social, reproductive, and disordered behavior circuits in the brain.

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“…These data build upon other findings that mitochondrial dysfunction and altered metabolism play a critical role in the regulation of social behaviors (Kanellopoulos et al, 2020; Miranda Mendonça et al, 2019; Picard et al, 2018), suggesting that altered microglial mitochondrial function may regulate the establishment of complex social behaviors through alterations in synaptic regulation. Previous studies have demonstrated that microglial phagocytosis regulates the development of synaptic circuitry important for social behavior in the ACC during the time period surrounding our PN9 injection (Block et al, 2022). Given the importance of the ACC to regulation of social behaviors, and it’s implication in the etiology of various neurodevelopmental disorders (Block et al, 2022; Delmonte et al, 2013; Mague et al, 2020), we assessed microglial mitochondrial function within the ACC.…”

Section: Limitations Of the Studymentioning

confidence: 93%

“…Previous studies have demonstrated that microglial phagocytosis regulates the development of synaptic circuitry important for social behavior in the ACC during the time period surrounding our PN9 injection (Block et al, 2022). Given the importance of the ACC to regulation of social behaviors, and it’s implication in the etiology of various neurodevelopmental disorders (Block et al, 2022; Delmonte et al, 2013; Mague et al, 2020), we assessed microglial mitochondrial function within the ACC. While our studies revealed robust alterations in microglial mitochondrial function in the ACC, this study did not comprehensively characterize mitochondrial function from every region that may control these complex behaviors.…”

Section: Limitations Of the Studymentioning

confidence: 93%

Gonadal Hormones Impart Male-Biased Behavioral Vulnerabilities to Immune Activation via Microglial Mitochondrial Function

Bordt

Moya

et al. 2022

Preprint

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There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

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Prenatal environmental stressors impair postnatal microglia function and adult behavior in males

Cited by 51 publications

References 107 publications

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior

Gonadal Hormones Impart Male-Biased Behavioral Vulnerabilities to Immune Activation via Microglial Mitochondrial Function

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