Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

Rojas-Charry, Liliana; Nardi, Leonardo; Methner, Axel; Schmeißer, Michael J.

doi:10.1007/s00109-020-02018-2

Cited by 33 publications

(24 citation statements)

References 218 publications

(251 reference statements)

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“…Tshz3 loss in SCINs might also alter their morphofunctional properties and thereby indirectly impact gene expression in their striatal targets. Regarding the pathways dysregulated in the striatum of Camk2a-cKO mice, enrichment analysis highlights synaptic activity and mitochondrial function pathways, whose alterations are suggested to contribute to ASD development ( Citrigno et al, 2020 ; Rojas-Charry et al, 2021 ). In the same line, testing for enrichment of MGI mammalian phenotypes associated with the DEGs identified impaired coordination and hyperactivity, two behaviors that frequently accompany ASD.…”

Section: Discussionmentioning

confidence: 99%

Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

et al. 2021

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Camk2a-Cre mice have been widely used to study the postnatal function of several genes in forebrain projection neurons, including cortical projection neurons (CPNs) and striatal medium-sized spiny neurons (MSNs). We linked heterozygous deletion of TSHZ3/Tshz3 gene to autism spectrum disorder (ASD) and used Camk2a-Cre mice to investigate the postnatal function of Tshz3, which is expressed by CPNs but not MSNs. Recently, single-cell transcriptomics of the adult mouse striatum revealed the expression of Camk2a in interneurons and showed Tshz3 expression in striatal cholinergic interneurons (SCINs), which are attracting increasing interest in the field of ASD. These data and the phenotypic similarity between the mice with Tshz3 haploinsufficiency and Camk2a-Cre-dependent conditional deletion of Tshz3 (Camk2a-cKO) prompted us to better characterize the expression of Tshz3 and the activity of Camk2a-Cre transgene in the striatum. Here, we show that the great majority of Tshz3-expressing cells are SCINs and that all SCINs express Tshz3. Using lineage tracing, we demonstrate that the Camk2a-Cre transgene is expressed in the SCIN lineage where it can efficiently elicit the deletion of the Tshz3-floxed allele. Moreover, transcriptomic and bioinformatic analysis in Camk2a-cKO mice showed dysregulated striatal expression of a number of genes, including genes whose human orthologues are associated with ASD and synaptic signaling. These findings identifying the expression of the Camk2a-Cre transgene in SCINs lineage lead to a reappraisal of the interpretation of experiments using Camk2a-Cre-dependent gene manipulations. They are also useful to decipher the cellular and molecular substrates of the ASD-related behavioral abnormalities observed in Tshz3 mouse models.

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Section: Discussionmentioning

confidence: 99%

Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

et al. 2021

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“…In fact, it has been reported that up to 80% of individuals with ASD may also have MD (Rose et al, 2018). Neurons consume a large amount of energy to maintain ionic gradients and support neurotransmission (Li et al, 2004;Kann and Kovacs, 2007;Princz et al, 2018) so it is not surprising that mitochondrial defects have been implicated in both neurodevelopmental and neurodegenerative disorders (Lin and Beal, 2006;Rossignol and Frye, 2012;Burté et al, 2015;Rose et al, 2018;Johnson et al, 2021;Rojas-Charry et al, 2021). Inside neurons, mitochondria are the main energy producers and are integral in maintaining calcium homeostasis at the synapse, which is vital for regulating neurotransmission (Lin and Sheng, 2015).…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility

Victor

Donaldson

Johnson

et al. 2021

Front. Mol. Neurosci.

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Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). Children with PW-UPD are at higher risk for developing autism spectrum disorder (ASD) than the neurotypical population. In this study, we used expression analysis of PW-UPD neurons to try to identify the molecular cause for increased autism risk.Methods: Dental pulp stem cells (DPSC) from neurotypical control and PWS subjects were differentiated to neurons for mRNA sequencing. Significantly differentially expressed transcripts among all groups were identified. Downstream protein analysis including immunocytochemistry and immunoblots were performed to confirm the transcript level data and pathway enrichment findings.Results: We identified 9 transcripts outside of the PWS critical region (15q11.2-q13.1) that may contribute to core PWS phenotypes. Moreover, we discovered a global reduction in mitochondrial transcripts in the PW-UPD + ASD group. We also found decreased mitochondrial abundance along with mitochondrial aggregates in the cell body and neural projections of +ASD neurons.Conclusion: The 9 transcripts we identified common to all PWS subtypes may reveal PWS specific defects during neurodevelopment. Importantly, we found a global reduction in mitochondrial transcripts in PW-UPD + ASD neurons versus control and other PWS subtypes. We then confirmed mitochondrial defects in neurons from individuals with PWS at the cellular level. Quantification of this phenotype supports our hypothesis that the increased incidence of ASD in PW-UPD subjects may arise from mitochondrial defects in developing neurons.

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“…Veh-K/W transcripts also displayed downregulation of mitochondria- and ECM-related genes. Mitochondrial dysfunction has been associated with synapse dysregulation ( Li et al, 2004 ; Vos et al, 2010 ; Sheng and Cai, 2012 ; Lee et al, 2018 ) as well as ASD ( Hollis et al, 2017 ; Frye, 2020 ; Rojas-Charry et al, 2021 ). It is possible that the upregulation of synaptic genes in the context of a reverse-ASD pattern in Shank2 -KO mice might be related to decreased mitochondrial gene expression.…”

Section: Discussionmentioning

confidence: 99%

Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

Yoo

Lee

Kim

et al. 2021

Front. Mol. Neurosci.

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Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change – increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7–21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type–specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.

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Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

Cited by 33 publications

References 218 publications

Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility

Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

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