Zobraziť v EDS

CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility

Uložené v:
Podrobná bibliografia
Názov: CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility
Autori: Awad, Patricia Nora, Zerbi, Valerio, Johnson-Venkatesh, Erin M, Damiani, Francesca, Pagani, Marco, Markicevic, Marija, Nickles, Sarah, Gozzi, Alessandro, Umemori, Hisashi, Fagiolini, Michela
Zdroj: Mol Psychiatry
Molecular Psychiatry, 29 (6)
Molecular Psychiatry
Informácie o vydavateľovi: Springer Science and Business Media LLC, 2023.
Rok vydania: 2023
Predmety: Neuroscience, Autism spectrum disorders, Magnetic Resonance Imaging / methods, Male, 0301 basic medicine, Neurodevelopmental Disorders / genetics, Corpus Callosum / metabolism, Protein Serine-Threonine Kinases, Cognitive Dysfunction / physiopathology, Epileptic Syndromes / physiopathology, Gyrus Cinguli, Article, Neurodevelopmental Disorders / metabolism, Corpus Callosum, Mice, 03 medical and health sciences, Cognition, 0302 clinical medicine, X-Linked Intellectual Disability, Synapses / physiology, Animals, Gyrus Cinguli / metabolism, Cognitive Dysfunction, Cognition / physiology, X-Linked Intellectual Disability / physiopathology, X-Linked Intellectual Disability / genetics, Mice, Knockout, Neurons, Neurons / metabolism, Brain, Protein Serine-Threonine Kinases / genetics, Synapses / metabolism, Magnetic Resonance Imaging, Spasms, Infantile / metabolism, Spasms, Infantile / physiopathology, Mice, Inbred C57BL, Disease Models, Animal, Cognitive Dysfunction / metabolism, Spasms, Infantile / genetics, Neurodevelopmental Disorders, Protein Serine-Threonine Kinases / metabolism, Cognitive Dysfunction / genetics, Epileptic Syndromes / genetics, Synapses, Brain / metabolism, Female, Epileptic Syndromes, Spasms, Infantile, Neurodevelopmental Disorders / physiopathology, CDKL5 Deficiency Disorder
Popis: Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.
Druh dokumentu: Article
Other literature type
Popis súboru: application/pdf; application/application/pdf
Jazyk: English
ISSN: 1476-5578
1359-4184
DOI: 10.1038/s41380-023-01962-y
DOI: 10.3929/ethz-b-000601551
Prístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/36737483
https://archive-ouverte.unige.ch/unige:185366
https://doi.org/10.1038/s41380-023-01962-y
http://hdl.handle.net/20.500.11850/601551
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Prístupové číslo: edsair.doi.dedup.....40a30ed94541d7d7f268db5c65c269e4
Databáza: OpenAIRE
Popis
Abstrakt:Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.
ISSN:14765578
13594184
DOI:10.1038/s41380-023-01962-y