Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment

Fernandez, Alejandra; Meechan, Daniel W.; Karpinski, Beverly A.; Paronett, Elizabeth M.; Bryan, Corey A.; Rutz, H.L.H.; Radin, Eric A.; Lubin, Noah; Bonner, Erin R; Popratiloff, Anastas; Rothblat, Lawrence A.; Maynard, Thomas M.; LaMantia, Anthony‐Samuel

doi:10.1016/j.neuron.2019.04.013

Cited by 127 publications

(125 citation statements)

References 71 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…It is noteworthy that the terms related to synaptic components were significantly enriched, such as GABA-ergic synapse, axon, cell adhesion, and cell morphogenesis, indicating that the dysfunction of synapses could be one key pathological basis of ASD, which is a commonly accepted viewpoint in the field [Gokoolparsadh et al, 2016]. In addition, genes involved in NADH dehydrogenase (ubiquinone) activity were enriched in overlapped DEGs, in agreement with the previous finding that mitochondrial dysfunction is involved in ASD and intellectual disorder [Goh, Dong, Zhang, DiMauro, & Peterson, 2014;Fernandez et al, 2019].…”

Section: Functional Annotation and Pathway Enrichment Of The Overlappsupporting

confidence: 88%

“…The functions of module 1 and module 2 have been clearly linked to the pathomechanism of ASD [Gokoolparsadh et al, ]. For the module 3, mitochondrial dysfunction has recently been reported to cause cortical under‐connectivity and cognitive impairment in neurodevelopmental disorders [Fernandez et al, ]. In the Cortex‐Juvenile network (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These biological processes have been reported to be essential for various aspects of the nervous system, such as neurodevelopment, behavior, synaptic plasticity, axon pathfinding, and so forth, many of which have been associated with ASD. Interestingly, dysfunction of mitochondria, calcium and MAPK and cAMP signaling pathway have been reported to associate with abnormal synaptic plasticity [Fernandez et al, ; Booker et al, ; Vithayathil, Pucilowska, & Landreth, ; Cui et al, ; Zamarbide et al, ]. It is possible that the different transcriptional factors may result in ASD by the final dysfunction of synapses.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

View full text Add to dashboard Cite

Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

show abstract

Section: Functional Annotation and Pathway Enrichment Of The Overlappsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

View full text Add to dashboard Cite

show abstract

“…This contrast between in vivo and in vitro data suggests that the effects of the 22q11.2 deletion on barrier function are not solely due to claudin-5 gene dosage, but more likely due to an interaction of genes in the deleted region or an exaggerated stress response in vitro. Of note are the 6 mitochondrial genes in the 22q11.2 deleted region (Maynard et al, 2008;Napoli et al, 2015), which may further contribute to compromise the BBB given the impaired mitochondrial function reported in other CNS cell populations in 22qDS (Fernandez et al, 2019;Li, Ryan, et al, in press). Furthermore, we have found that ICAM-1 is upregulated in the BBB, implicating differences in inflammatory/stress responses in 22qDS (Alvarez, Cayrol, et al, 2011;Daneman & Prat, 2014;Dietrich, 2002).…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Crockett

Ryan

Vásquez

et al. 2019

Preprint

View full text Add to dashboard Cite

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ).As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease. 4

show abstract

“…Mitochondrial dysfunction has also been recently demonstrated to lead to significant reductions in long range axonal connectivity. 55 Because structural connectivity is a required substrate for functional connectivity, OXT-induced changes in factors affecting anatomical connections between neurons could affect functional brain network organization (i.e., segregation and integration). Our general finding of impaired cortical functional connectivity in male offspring treated with OXT is broadly supportive of this notion.…”

Section: Discussionmentioning

confidence: 99%

Transient uterine hypercontractility causes fetal cerebral oxidative stress and enduring mitochondrial and behavioral abnormalities in adolescent male rat offspring

Palanisamy¹,

Giri²,

Jiang³

et al. 2019

Preprint

View full text Add to dashboard Cite

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI imaging, we confirmed that oxytocininduced aberrant uterine hypercontractility significantly compromised uteroplacental perfusion.This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 h after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring.Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed malespecific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders. 8.2.1; GraphPad Software Inc.), behavioral data with SYSTAT12 (Chicago, IL), and fcOISI data with MATLAB. Study approval:All experiments reported here were approved by the Institutional Animal Care and Use Committee at Washington University in St. Louis (#20170010) and comply with the ARRIVE guidelines. Author contributionsAP conceived the study design, planned the experiments, and wrote the manuscript with help from all co-authors. AP, TG and JJ developed the OXT dosing paradigm and conducted the molecular biology experiments. JDQ and JRG performed the placental imaging experiments, analyzed the data, and helped draft the manuscript. SBC performed the behavioral experiments, and SEM and DFW conducted the analysis and helped with interpretation and drafting of the manuscript. AB and AQB collected, analyzed, and interpreted the fcOISI data, and helped write the manuscript.

show abstract

Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment

Cited by 127 publications

References 71 publications

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Transient uterine hypercontractility causes fetal cerebral oxidative stress and enduring mitochondrial and behavioral abnormalities in adolescent male rat offspring

Contact Info

Product

Resources

About