Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation in mice

Guma, Elisa; Snook, Emily; Spring, Shoshana; Lerch, Jason P.; Nieman, Brian J.; Devenyi, Gabriel A.; Chakravarty, M. Mallar

doi:10.1016/j.nicl.2021.102868

Cited by 11 publications

(13 citation statements)

References 63 publications

(70 reference statements)

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“…Overall, this analysis suggests that there may be interesting sex differences underlying the neurodevelopmental abnormalities associated MIA and THC exposure. This dimensional approach may parse variability better than categorical approaches (89) and has proven successful in our previous work (7,17,28)…”

Section: Discussionmentioning

confidence: 94%

“…Structural images were visually inspected for quality (3 removed due to motion or hydrocephalus, yielding n=242 images). Images were processed using a longitudinal two-level deformation based morphometry technique using the ANTs toolkit (http://stnava.github.io/ANTs/) for linear and non-linear registration (27) as described in our previous work (28) ( Supplement 1.4 ).…”

Section: Methodsmentioning

confidence: 99%

“…Offspring were then randomly assigned to receive daily injections (i.p.) of THC (1:1:18 THC 5 mg/kg [Cayman Chemicals], cremophor [Sigma Aldrich], saline solution) or vehicle (1:18 cremophor:saline) throughout the adolescent period (PND [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. The dosage was chosen to model moderate daily use, with a potency roughly equivalent to one average-sized cannabis cigarette ("joint") with 11% THC content, scaled to the weight of the mouse (18)(19)(20) (weight data in supplement 1.5.1, 2.3 & supplementary figure S1).…”

Section: Animalsmentioning

confidence: 99%

“…In this study, we leverage the strategy of performing longitudinal assays of the brain using in vivo magnetic resonance imaging (MRI) throughout development, and multi-behavioural testing in adulthood to investigate the potential synergistic effects of prenatal MIA-exposure in early gestation (GD9), followed by chronic adolescent THC exposure (postnatal day [PND] 28–45) in mice. Our previous work demonstrated that exposure to MIA alone leads to neuroanatomical remodeling in fetal stages (17) persisting to neurodevelopmental and behavioural abnormalities that appeared in adolescence and normalized by adulthood (7).…”

Section: Introductionmentioning

confidence: 99%

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Investigating the “two-hit hypothesis”: effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice

Guma

Cupo

et al. 2022

Preprint

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Background: Prenatal exposure to maternal immune activation (MIA) and chronic adolescent cannabis use are both risk factors for neuropsychiatric disorders. However, exposure to a single risk factor may not result in major mental illness, indicating that multiple exposures may be required for illness onset. Here, we examine whether combined exposure to prenatal MIA and adolescent delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, lead to enduring neuroanatomical and behavioural changes in adulthood. Methods: Mice were prenatally exposed to viral mimetic, poly I:C (5mg/kg), or vehicle at gestational day (GD)9, and postnatally exposed to chronic THC (5mg/kg, intraperitoneal) or vehicle during adolescence (postnatal day [PND]28-45). Longitudinal magnetic resonance imaging (MRI) was performed pre-treatment, PND25, post-treatment, PND50, and in adulthood, PND85, followed by behavioural tests for anxiety-like, social, and sensorimotor gating. Post-mortem assessment of cannabinoid (CB)1 and 2 receptor expressing cells was performed in altered regions identified by MRI (anterior cingulate and somatosensory cortices, striatum, and hippocampus). Results: Subtle deviations in neurodevelopmental trajectory and subthreshold anxiety-like behaviours were observed in mice exposed to both risk factors. Sex-dependent effects were observed in patterns of shared brain-behaviour covariation, indicative of potential sex differences in response to MIA and THC. Density of CB1 and CB2 receptor positive cells was significantly decreased in all mice exposed to MIA, THC, or both. Conclusions: These findings suggest that there may be a cumulative effect of risk factor exposure on gross neuroanatomical development, and that the endocannabinoid system may be sensitive to both prenatal MIA, adolescent THC, or the combination.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigating the “two-hit hypothesis”: effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice

Guma

Cupo

et al. 2022

Preprint

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“…Exposure to poly I:C at the dose selected (5 mg/kg) typically elicits an acute immune response peaking 3 to 4 h postinjection, resolving, typically, within 24 to 48 h ( 60 ). We chose this dose and administration to model a more acute inflammatory exposure and to match our previous work ( 11 , 61 ). Some of the differences in MIA-exposed offspring may be due to differences in developmental stage of the fetus (discussed in greater detail below) or to the maternal milieu.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Guma

Bordeleau

Ibáñez

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Prenatal exposure to maternal infection increases the risk of developing mental health disorders, such as schizophrenia and autism spectrum disorder. Exposure to maternal immune activation has been associated with a number of neuroanatomical deficits in adolescent and adult offspring, with differing effects based on the gestational timing of infection. However, little is known about how the embryo brain is affected. We show, using whole-brain MRI, that maternal immune activation significantly affects brain anatomy. When the exposure occurs early in pregnancy, volume reductions are mainly observed, while the opposite is true for exposure later in pregnancy. Furthermore, we identify alterations to the density of certain classes of neurons and glia, which have been associated with stress and inflammation in the brain.

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Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

et al. 2022

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The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

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Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation in mice

Cited by 11 publications

References 63 publications

Investigating the “two-hit hypothesis”: effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice

Investigating the “two-hit hypothesis”: effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

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