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Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome / Magdalena KALINOWSKA in Molecular Autism, 13 (2022)
[article]
Titre : Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/metabolism Disease Models, Animal Fragile X Mental Retardation Protein/genetics/metabolism Fragile X Syndrome/genetics/metabolism/pathology Mice Mice, Knockout Neurons/metabolism/pathology Parvalbumins/metabolism RNA, Messenger/metabolism Somatostatin/metabolism Autism Behavior Fmrp Fragile X syndrome Inhibitory neurons Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Molecular Autism > 13 (2022) . - 29 p.[article] Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome [Texte imprimé et/ou numérique] / Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur . - 29 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 29 p.
Mots-clés : Animals Autism Spectrum Disorder/metabolism Disease Models, Animal Fragile X Mental Retardation Protein/genetics/metabolism Fragile X Syndrome/genetics/metabolism/pathology Mice Mice, Knockout Neurons/metabolism/pathology Parvalbumins/metabolism RNA, Messenger/metabolism Somatostatin/metabolism Autism Behavior Fmrp Fragile X syndrome Inhibitory neurons Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 Imbalance of laminar-specific excitatory and inhibitory circuits of the orbitofrontal cortex in autism / Xuefeng LIU in Molecular Autism, 11 (2020)
[article]
Titre : Imbalance of laminar-specific excitatory and inhibitory circuits of the orbitofrontal cortex in autism Type de document : Texte imprimé et/ou numérique Auteurs : Xuefeng LIU, Auteur ; Julied BAUTISTA, Auteur ; Edward LIU, Auteur ; Basilis ZIKOPOULOS, Auteur Article en page(s) : 83 p. Langues : Anglais (eng) Mots-clés : Amygdala Calbindin Calretinin Cortical layers Emotions Inhibitory neurons Myelinated axons Parvalbumin Prefrontal cortex Social interactions Index. décimale : PER Périodiques Résumé : BACKGROUND: The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion-based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC, as well as how the circuit is disrupted in individuals with autism spectrum disorder (ASD). METHODS: We used post-mortem brain tissue from neurotypical adults and individuals with ASD. We examined the morphology and distribution of myelinated axons across cortical layers in OFC, at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of all neurons and neurochemically- and functionally-distinct inhibitory neurons that express the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR). RESULTS: We found that the density of myelinated axons increased consistently towards layer 6, while the average axon diameter did not change significantly across layers in both groups. However, both the density and diameter of myelinated axons were significantly lower in the ASD group compared with the Control group. The distribution pattern and density of the three major types of inhibitory neurons was comparable between groups, but there was a significant reduction in the density of excitatory neurons across OFC layers in ASD. LIMITATIONS: This study is limited by the availability of human post-mortem tissue optimally processed for high-resolution microscopy and immunolabeling, especially from individuals with ASD. CONCLUSIONS: The balance between excitation and inhibition in OFC is at the core of its function, assessing and integrating emotional and social cues with internal states and external inputs. Our preliminary results provide evidence for laminar-specific changes in the ratio of excitation/inhibition in OFC of adults with ASD, with an overall weakening and likely disorganization of excitatory signals and a relative strengthening of local inhibition. These changes likely underlie pathology of major OFC communications with limbic or other cortices and the amygdala in individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for social interactions and emotions in autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00390-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433
in Molecular Autism > 11 (2020) . - 83 p.[article] Imbalance of laminar-specific excitatory and inhibitory circuits of the orbitofrontal cortex in autism [Texte imprimé et/ou numérique] / Xuefeng LIU, Auteur ; Julied BAUTISTA, Auteur ; Edward LIU, Auteur ; Basilis ZIKOPOULOS, Auteur . - 83 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 83 p.
Mots-clés : Amygdala Calbindin Calretinin Cortical layers Emotions Inhibitory neurons Myelinated axons Parvalbumin Prefrontal cortex Social interactions Index. décimale : PER Périodiques Résumé : BACKGROUND: The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion-based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC, as well as how the circuit is disrupted in individuals with autism spectrum disorder (ASD). METHODS: We used post-mortem brain tissue from neurotypical adults and individuals with ASD. We examined the morphology and distribution of myelinated axons across cortical layers in OFC, at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of all neurons and neurochemically- and functionally-distinct inhibitory neurons that express the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR). RESULTS: We found that the density of myelinated axons increased consistently towards layer 6, while the average axon diameter did not change significantly across layers in both groups. However, both the density and diameter of myelinated axons were significantly lower in the ASD group compared with the Control group. The distribution pattern and density of the three major types of inhibitory neurons was comparable between groups, but there was a significant reduction in the density of excitatory neurons across OFC layers in ASD. LIMITATIONS: This study is limited by the availability of human post-mortem tissue optimally processed for high-resolution microscopy and immunolabeling, especially from individuals with ASD. CONCLUSIONS: The balance between excitation and inhibition in OFC is at the core of its function, assessing and integrating emotional and social cues with internal states and external inputs. Our preliminary results provide evidence for laminar-specific changes in the ratio of excitation/inhibition in OFC of adults with ASD, with an overall weakening and likely disorganization of excitatory signals and a relative strengthening of local inhibition. These changes likely underlie pathology of major OFC communications with limbic or other cortices and the amygdala in individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for social interactions and emotions in autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00390-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433