1. Introduction: MIA, mitochondria and brain development
2. The developing brain: role of mitochondria
2.1 Overview of human brain development
2.2 Overview of the mitochondrial biology system
2.3 Obligatory role for mitochondrial function in brain development
2.3.1 In neurogenesis
2.3.2 In glial cell development
2.3.3 In the development of the blood-brain barrier (BBB)
2.3.4 In axonal development
2.3.5 In synaptogenesis
3. Inflammation and mitochondrial function: focus on the intrauterine period
3.1 Immune mediators and mitochondrial function
3.2 Mitochondrial dysfunction as a mediator of preclinical MIA-related effects on the developing brain
|First Author||Year||Animal Model||MIA Protocol||Mitochondrial Effects in the Brain||Brain/Behavior Phenotypes|
|Briscoe, T. (|
|2006||Ovine||Prenatal exposure: Gestational day (GD) 95 intravenous bolus dose of lipopolysaccharide (LPS; 1μg/kg) vs. control (saline) directly to fetus (catheter); MIA validation: Direct fetal exposure via catheter, with demonstrated rise in cytokines.||↑oxidative stress in the parietal, temporal, occipital, and thalamus‐basal ganglia regions (measured by ↑lipid peroxide production and 8-Isoprostane) and in the placenta|
|Zhu, Y. (|
|2007||Sprague-Dawley rats||Prenatal exposure: GD 10.5 intraperitoneal (i.p). injection of LPS (10,000 endotoxin units/kg) vs. control (saline); Postnatal exposure (in separate animals without prenatal exposure): 4 months post-natal acute supranigral injection of LPS (10μg/4μl in saline) vs. control (saline); MIA validation: Not described.||↑oxidative stress in the midbrain (measured by ↓ glutathione (GSH) and ↑ in oxidized GSH and lipid peroxide production) [in both prenatal and postnatal LPS exposure groups]||Brain: ↓DA neuron count in the substantia nigra|
|Doehner, J. (|
|2012||C57BL/6J mice||Prenatal exposure: GD17 intravenous injection of Poly(I:C) (5mg/kg) vs. control (saline); MIA validation: Not described.||↑mito density/content in reelin-positive granules in the hippocampus||Brain: ↑size and number of reelin-immunoreactive deposits (accumulation of aggregation-prone proteins and peptides)- associated with neuritic swellings|
|Naviaux, R.K. (|
|2013||C57BL/6J mice||2 Prenatal exposure groups: 1) Single dose i.p. injection of Poly(I:C) on GD12.5 (2 mg/kg); 2) Double dose i.p. injection of Poly(I:C) on GD12.5 (3 mg/kg) & GD17.4 (1.5 mg/kg); all vs. control group (saline) [all results are reported as 2 groups combined]; Postnatal Therapy: 6 weeks postpartum received weekly suramin injection; MIA validation: Not described.||↑mito bioenergetic function in the cerebrum (measured by ↑ complex I and IV activity; no change in Complex II, III activity or complex protein levels) [induced by Poly(I:C) and corrected by APT therapy] No change in mito density/content (measured by citrate synthase)||Behavior: ↓social preference, ↓sensorimotor coordination; Brain: ↓cerebellar purkinje cell, ultrastructural synaptic dysmorphology, ERK1/2 and CAMKII signal transduction abnormalities. [All are induced by Poly(I:C) and rescued by APT treatment]|
|Farrelly, L. (|
|2015||Wistar rats||Prenatal exposure: G15 intravenous injection of Poly(I:C) (4 mg/kg) vs. control (saline); Postnatal Therapy: Postnatal Day (PND) 34–47 i.p. daily injection of risperidone (0.045 mg/kg) vs. control (saline); MIA validation: Not described.||↑ mito bioenergetic proteins in the prefrontal cortex (PFC) (measured in unbiased proteomics: top 2 significantly different pathways were related to primarily ↑mitochondrial OXPHOS and tricarboxylic acid cycle (TCA cycle) proteins) [induced by Poly(I:C) with some reversed by risperidone treatment]||Brain: Measured 7 myelin and myelin-related proteins in the PFC, 2 were altered by Poly(I:C) (measured in hypothesis driven proteomics analysis- isoform 3 of myelin basic protein and rhombex 29 were altered by Poly(I:C)).|
|Al-Amin, M.M. (|
|2016||Swiss albino mice||Prenatal exposure: GD 16 i.p. injection of LPS (50 μg/kg) vs. control (water); MIA validation: Not described.||↑oxidative stress that is age and brain region specific (measured on PND 1- ↑ GSH level, ↓superoxide dismutase activity; PND 7- ↑advanced oxidation of protein product level; PND 14- ↑lipid peroxidation (MDA) and activity of catalase; PND 21- ONLY ↑MDA remains (across all brain regions measured: hippocampus and cerebellum, cortex)|
|Györffy, B.A. (|
|2016||Wistar rats||Prenatal exposure: GD 13.5 i.p. injection of LPS (20 μg/kg) vs. control (saline); MIA validation: Demonstrated rise in rectal temperature of dams 3hrs post LPS injection.||Altered proteins in energy homeostasis/carbohydrate metabolism (proxy for mito bioenergetic function) Altered proteins in oxidative stress||Brain: Altered proteins in neurite outgrowth/cytoskeleton and synaptic vesicle exo- and endocytosis.|
|Swanepoel, T. (|
|2018||Sprague-Dawley rats||Prenatal exposure: GD15-16 subcutaneous injection of LPS (100 μg/kg) vs. control (saline); Postnatal challenge & therapy: Postnatal day (PND) 35-50 methamphetamine (MA) with N-acetyl cysteine (NAC) treatment vs control PND 51-64; MIA validation: Not described.||↑oxidative stress in the frontal cortical and striatum (measured by ↑MDA, marker of lipid peroxidation) and ↑in plasma ROS [in both prenatal LPS exposure and LPS + 2nd hit postnatal MA exposure groups; All reversed by NAC therapy]||Behavior: ↑social withdrawal, ↓recognition memory, deficit in prepulse inhibition [induced by LPS and LPS+MA; reversed by (mostly) NAC]; Brain: ↑frontal cortical dopamine and noradrenaline [induced by LPS and LPS+MA; reversed by NAC]|
|Robicsek, O. (|
|2018||Wistar rats (in-vivo model); see manuscript for in-vitro model||Prenatal exposure: GD15, injected into the tail vein with poly-I:C (4 mg/kg/ml) vs. control (saline); Postnatal therapy: PNDs 34–46 isolated active normal mitochondria (IAN-MIT) (100 μg/4.5μl), injected into the medial prefrontal cortex; MIA validation: Not described.||↓mito bioenergetic function in frontal cortex neurons (measured by mitochondrial membrane potential (MMP)) [induced by Poly(I:C) and rescued by IAN-MIT therapy] No change in mitochondrial distribution and network connectivity||Behavior: Latent inhibition was absent in Poly(I:C) exposed mice, but was rescued by IAN-MIT postnatal therapy.|
|Cieślik, M. (|
|2020||Wistar rats||Prenatal exposure: GD9.5 i.p. injection of LPS (100 μg/kg) vs. control (saline); MIA validation: Demonstrated maternal sickness behavior up to 24hrs post LPS injection.||Altered mitochondrial structure/morphology in cerebral cortex (measured by ultrastructural changes (cristae blurring)) ↑oxidative stress in the cerebral cortex (measured by ↑12-lipoxygenase and cyclooxygenase-2 mRNA levels, ↑DCF fluorescence (to quantify ROS), ↑oxidized GSH (GSSG),↓GSH/GSSG ratio)||Behavior: ↑ heterogeneity in intensity of play behavior, ↓social interaction (no change in locomotor and exploratory activity, anxiety-related behavior); Brain: ↓Formation and turnover of synaptic vesicles (protein levels), disturbed synaptic membranes & changed myelin (via ultrastructural measurement)|
|Anderson, A. (|
|2021||Wild type (WT) rats|
(see manuscript for transgenic models)
|Prenatal exposure: GD12.5 i.p. injection of Poly(I:C) (100 μL/10g) vs. control (saline) [Poly(I:C) exposure given to WT and transgenic mice- only WT discussed here]; MIA validation: Not described, but cite previous studies conducted by lab with demonstrated cytokine rise.||Altered energy metabolism and acylcarnitine species in the neocortex (authors argue proxy for mitochondrial metabolism)|
|Cieślik, M. (|
|2021||Wistar rats||Prenatal exposure: GD9.5 i.p. injection of LPS (100 μg/kg) vs. control (saline); MIA validation: Demonstrated maternal sickness behavior up to 24hrs post LPS injection.||↓mito bioenergetic function in the hippocampus (measured by ↓ gene expression for Complex I (mt-Nd1) and Complex IV (mt-Co1), ↓protein level for ND1 (CI), ↓ CI enzyme activity (no change CIV), and ↓ MMP) Altered mitochondrial structure/morphology in the hippocampus (measured by ultrastructural changes of synaptic mitochondria ("swollen" mitochondria) ↑oxidative stress in the hippocampus (measured by ↓reduced/oxidized glutathione ratio (indicates enhanced generation of ROS); ↓ total GSH; ↑oxidized DCF (proxy for ROS); ↓mito antioxidant enzymes(Sod1 and Sod2))||Brain: ↑ size of synaptic cleft (no change in size and # of synaptic vesicles (SVs)), ultrastructural changes in synapses (↓packing density of SVs in the presynaptic area, blurred and thickened structure of the synaptic cleft), altered synaptic proteins|
3.3 Mitochondrial dysfunction in the context of human neurodevelopmental disorders
- Nguyen Nguyen H.T.
- Kato H.
- Sato H.
- Yamaza H.
- Sakai Y.
- Ohga S.
- et al.
- Nguyen Nguyen H.T.
- Kato H.
- Sato H.
- Yamaza H.
- Sakai Y.
- Ohga S.
- et al.
- Nguyen Nguyen H.T.
- Kato H.
- Sato H.
- Yamaza H.
- Sakai Y.
- Ohga S.
- et al.
- Nguyen Nguyen H.T.
- Kato H.
- Sato H.
- Yamaza H.
- Sakai Y.
- Ohga S.
- et al.
4. Conclusions and future directions
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The preparation of this paper was supported, in part, by US PHS (NIH) grants US PHS (NIH) grants K99 HD097302, R01 HD-060628, R01 MH-105538, UH3 OD-023349 and ERC grants ERC-Stg 639766, ERC-Stg 678073.
The authors report no biomedical financial interests or potential conflicts of interest.
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