The epigenetic role of the Kleefstra syndrome protein EHMT1 in synaptic scaling and in cognition
Annotation
Radboud University, 23 mei 2017
Promotor : Bokhoven, J.H.L.M. van Co-promotores : Nadif Kasri, N., Zhou, H.
Publication type
Dissertation
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Organization
Cognitive Neuroscience
Subject
Donders Center for Medical Neuroscience; Radboudumc 7: Neurodevelopmental disorders; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical NeuroscienceAbstract
The contribution of epigenetic factors in controlling the expression of genetic programs related to cognition
and development posed a novel fascinating research challenge. Epigenetic factors, in general, are involved
in translating environmental stimuli and transducing a controlled response via modulation of gene
expression. In the recent years, epigenetic mechanisms were described to be required for neurobiological
processes like synaptic plasticity, cognition, brain development and psychiatric disorders. Interestingly,
mutation in genes that encode for epigenetic factors were described to be causative for numerous
neurodevelopmental disorders such as Intellectual disabilities and Autism spectrum disorders. In Nijmegen,
Kleefstra and collaborators, in the last decade described for the first time a mutation in the Euchromatic
histone methyl-transferase 1 (EHMT1) gene, that is causative for a neurodevelopmental disorder
denominated as Kleefstra syndrome (KS).
The findings presented in this research thesis relate to functional studies of the KS gene EHMT1 in
regulating synaptic homeostasis and hippocampal pattern separation. By combining a diverse array of
genetic and pharmacological manipulations of EHMT1 expression and function in a construct-validated
mouse model for KS and in neurons derived from human pluripotent stem cells (hiPSCs) directly from KS-
patients, new roles of EHMT1 function in regulating homeostatic synaptic scaling and pattern separation in
the hippocampus are described. The findings here outlined extended our understanding of the
pathophysiology related to KS at a molecular and physiological level. In parallel, the studies here presented
contributed to advance scientific knowledge of the role of epigenetic factors in regulating synaptic, cognitive
and neurodevelopmental processes, that can be used for future studies related to KS and the epigenetic
regulation of nervous system function and development.
This item appears in the following Collection(s)
- Academic publications [238441]
- Dissertations [13444]
- Electronic publications [122523]
- Faculty of Medical Sciences [90373]
- Open Access publications [97518]
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