Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder / Laura SIMÕES DE OLIVEIRA in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 28p. Titre : Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder Type de document : texte imprimé Auteurs : Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R. LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J.A. WYLLIE, Auteur ; Peter C. KIND, Auteur Article en page(s) : 28p. Langues : Anglais (eng) Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder [texte imprimé] / Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R. LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J.A. WYLLIE, Auteur ; Peter C. KIND, Auteur . - 28p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 28p. Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

FMRP and the Pathophysiology of Fragile X Syndrome / Stephanie A. BARNES  

Public ISBD in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA Titre : FMRP and the Pathophysiology of Fragile X Syndrome Type de document : texte imprimé Auteurs : Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur Année de publication : 2016 Importance : p.113-128 Langues : Anglais (eng) Mots-clés : ERK  FMR1  FMRP  Fragile X  mGluR1/5  Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA FMRP and the Pathophysiology of Fragile X Syndrome [texte imprimé] / Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur . - 2016 . - p.113-128. Langues : Anglais (eng) Mots-clés : ERK  FMR1  FMRP  Fragile X  mGluR1/5  Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301

Exemplaires(0)

Disponibilité
aucun exemplaire

Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? / Talakad LOHITH in Molecular Autism, (May 2013)  

Public ISBD [article]  inMolecular Autism > (May 2013) . - 8 p. Titre : Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? Type de document : texte imprimé Auteurs : Talakad LOHITH, Auteur ; Emily K. OSTERWEIL, Auteur ; Masahiro FUJITA, Auteur ; Kimberly JENKO, Auteur ; Mark F. BEAR, Auteur ; Robert INNIS, Auteur Année de publication : 2013 Article en page(s) : 8 p. Langues : Anglais (eng) Mots-clés : Fragile X mental retardation protein  Fragile X syndrome  Glutamate receptor  mGluR5  Receptor density  Receptor expression Index. décimale : PER Périodiques Résumé : BACKGROUND:Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown.METHODS:Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [3H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand's dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression.RESULTS:The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression.CONCLUSIONS:Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder. En ligne : http://dx.doi.org/10.1186/2040-2392-4-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? [texte imprimé] / Talakad LOHITH, Auteur ; Emily K. OSTERWEIL, Auteur ; Masahiro FUJITA, Auteur ; Kimberly JENKO, Auteur ; Mark F. BEAR, Auteur ; Robert INNIS, Auteur . - 2013 . - 8 p. Langues : Anglais (eng) in Molecular Autism > (May 2013) . - 8 p. Mots-clés : Fragile X mental retardation protein  Fragile X syndrome  Glutamate receptor  mGluR5  Receptor density  Receptor expression Index. décimale : PER Périodiques Résumé : BACKGROUND:Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown.METHODS:Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [3H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand's dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression.RESULTS:The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression.CONCLUSIONS:Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder. En ligne : http://dx.doi.org/10.1186/2040-2392-4-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

---

1 (1 - 3 / 3) Par page : 25 50 100 200