Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.

Animals Long-Term Potentiation Receptors, N-Methyl-D-Aspartate / metabolism Receptors, AMPA / metabolism Spasms, Infantile / genetics Disease Models, Animal Rats Protein Serine-Threonine Kinases / metabolism Hippocampus / metabolism Pyramidal Cells / metabolism Male CA1 Region, Hippocampal / metabolism Epileptic Syndromes / genetics Genetic Diseases, X-Linked / genetics Synapses / metabolism Excitatory Postsynaptic Potentials
AMPA receptor CDKL5 NMDA receptor hippocampus intrinsic properties rat synaptic plasticity

Journal

Molecular autism
ISSN: 2040-2392
Titre abrégé: Mol Autism
Pays: England
ID NLM: 101534222

Informations de publication

Date de publication:
14 Jun 2024
Historique:
received: 03 11 2023
accepted: 07 05 2024
medline: 15 6 2024
pubmed: 15 6 2024
entrez: 14 6 2024
Statut: epublish

Résumé

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 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. Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 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. 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.

Sections du résumé

BACKGROUND 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
METHODS 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 RESULTS
Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5
CONCLUSIONS 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 CONCLUSIONS
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.

Identifiants

DOI: 10.1186/s13229-024-00601-9 PMID: 38877552
pubmed: 38877552
doi: 10.1186/s13229-024-00601-9
pii: 10.1186/s13229-024-00601-9
doi:

Substances chimiques

Receptors, N-Methyl-D-Aspartate 0
Receptors, AMPA 0
Protein Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

28

Subventions

Organisme : NIMH NIH HHS
ID : T32 MH015442
Pays : United States
Organisme : Wellcome Trust
ID : 204954/Z/16/Z
Pays : United Kingdom
Organisme : Simons Foundation Autism Research Initiative
ID : 529085

Informations de copyright

© 2024. The Author(s).

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Auteurs

Laura Simões de Oliveira (L)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Heather E O'Leary (HE)

School of Medicine, University of Colorado, Denver, CO, USA.
Department of Pharmacology, University of Colorado Denver, 12800 East 19th Ave, Aurora, CO, 80045, USA.

Sarfaraz Nawaz (S)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, 560065, India.
Centre for Brain Development and Repair, Instem, Bangalore, India.

Rita Loureiro (R)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Elizabeth C Davenport (EC)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Paul Baxter (P)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.

Susana R Louros (SR)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Owen Dando (O)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.

Emma Perkins (E)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Julien Peltier (J)

Faculty of Medical Sciences, Newcastle University Biosciences Institute, Newcastle upon Tyne, NE2 4HH, UK.

Matthias Trost (M)

Faculty of Medical Sciences, Newcastle University Biosciences Institute, Newcastle upon Tyne, NE2 4HH, UK.

Emily K Osterweil (EK)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Giles E Hardingham (GE)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.

Michael A Cousin (MA)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
Centre for Brain Development and Repair, Instem, Bangalore, India.

Sumantra Chattarji (S)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, 560065, India.
Centre for Brain Development and Repair, Instem, Bangalore, India.

Sam A Booker (SA)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.

Tim A Benke (TA)

School of Medicine, University of Colorado, Denver, CO, USA. tim.benke@cuanschutz.edu.
Department of Pharmacology, University of Colorado Denver, 12800 East 19th Ave, Aurora, CO, 80045, USA. tim.benke@cuanschutz.edu.

David J A Wyllie (DJA)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK. david.j.a.wyllie@ed.ac.uk.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK. david.j.a.wyllie@ed.ac.uk.
Centre for Brain Development and Repair, Instem, Bangalore, India. david.j.a.wyllie@ed.ac.uk.
Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK. david.j.a.wyllie@ed.ac.uk.

Peter C Kind (PC)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK. p.kind@ed.ac.uk.
Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK. p.kind@ed.ac.uk.
Centre for Brain Development and Repair, Instem, Bangalore, India. p.kind@ed.ac.uk.
Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK. p.kind@ed.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Plasticité neuronale › Potentialisation à long terme › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs ionotropes du glutamate › Récepteurs du N-méthyl-D-aspartate › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs ionotropes du glutamate › Récepteur de l'AMPA › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Syndromes épileptiques › Spasmes infantiles › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Hippocampe › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Cellules › Neurones › Cellules pyramidales › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Hippocampe › Région CA1 de l'hippocampe › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Syndromes épileptiques › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies génétiques liées au chromosome X › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Synapses › Enhanced hippocampal LTP but normal NMDA...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Transmission synaptique › Potentiels synaptiques › Potentiels post-synaptiques excitateurs › Enhanced hippocampal LTP but normal NMDA...