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Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine / R. H. WICHERS in Molecular Autism, 12 (2021)
[article]
Titre : Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine Type de document : Texte imprimé et/ou numérique Auteurs : R. H. WICHERS, Auteur ; J. L. FINDON, Auteur ; A. JELSMA, Auteur ; V. GIAMPIETRO, Auteur ; V. STOENCHEVA, Auteur ; D. M. ROBERTSON, Auteur ; C. M. MURPHY, Auteur ; S. BLAINEY, Auteur ; G. MCALONAN, Auteur ; C. ECKER, Auteur ; K. RUBIA, Auteur ; D. G. M. MURPHY, Auteur ; Eileen DALY, Auteur Article en page(s) : 14 p. Langues : Anglais (eng) Mots-clés : Adult Antidepressive Agents, Tricyclic/therapeutic use Attention/drug effects Autistic Disorder/diagnostic imaging/drug therapy/physiopathology/psychology Brain/diagnostic imaging/physiopathology Cross-Over Studies Double-Blind Method Executive Function/drug effects Humans Magnetic Resonance Imaging Male Middle Aged Pilot Projects Thiazepines/therapeutic use Young Adult Autism spectrum disorder Executive functioning Serotonin Tianeptine fMRI grants from Lilly and Shire. The other authors declare that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms. En ligne : http://dx.doi.org/10.1186/s13229-021-00422-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 14 p.[article] Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine [Texte imprimé et/ou numérique] / R. H. WICHERS, Auteur ; J. L. FINDON, Auteur ; A. JELSMA, Auteur ; V. GIAMPIETRO, Auteur ; V. STOENCHEVA, Auteur ; D. M. ROBERTSON, Auteur ; C. M. MURPHY, Auteur ; S. BLAINEY, Auteur ; G. MCALONAN, Auteur ; C. ECKER, Auteur ; K. RUBIA, Auteur ; D. G. M. MURPHY, Auteur ; Eileen DALY, Auteur . - 14 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 14 p.
Mots-clés : Adult Antidepressive Agents, Tricyclic/therapeutic use Attention/drug effects Autistic Disorder/diagnostic imaging/drug therapy/physiopathology/psychology Brain/diagnostic imaging/physiopathology Cross-Over Studies Double-Blind Method Executive Function/drug effects Humans Magnetic Resonance Imaging Male Middle Aged Pilot Projects Thiazepines/therapeutic use Young Adult Autism spectrum disorder Executive functioning Serotonin Tianeptine fMRI grants from Lilly and Shire. The other authors declare that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms. En ligne : http://dx.doi.org/10.1186/s13229-021-00422-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling / Pauline MARTIN in Molecular Autism, 11 (2020)
[article]
Titre : TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling Type de document : Texte imprimé et/ou numérique Auteurs : Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur Article en page(s) : 2 p. Langues : Anglais (eng) Mots-clés : CRISPR/Cas9 Disease modeling Early neurodevelopment Induced pluripotent stem cells mek-erk1/2 MNK1/2-eIF4E Neural progenitor cells tsc1 Tuberous sclerosis complex mTORC1 Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which played no part in the present study. The other authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 2 p.[article] TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling [Texte imprimé et/ou numérique] / Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur . - 2 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 2 p.
Mots-clés : CRISPR/Cas9 Disease modeling Early neurodevelopment Induced pluripotent stem cells mek-erk1/2 MNK1/2-eIF4E Neural progenitor cells tsc1 Tuberous sclerosis complex mTORC1 Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which played no part in the present study. The other authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427