Journal Article

DZNE-2021-00550

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome

Briševac, D. ; Scholz, R. ; Du, D. ; Elagabani, M. N. ; Köhr, G. ; Kornau, H.-C. (Last author)DZNE*

2021
Wiley-Blackwell Oxford

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Please use a persistent id in citations: doi:10.1111/jnc.15230

Abstract: Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients’ brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP-bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP- or GDP-binding properties, and recorded hippocampal long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6-dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6-GTP levels and actin filament assembly were caused in wild-type neurons by RNAi-mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3-week-old mice interfered with mGluR-LTD in wild-type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS.

Keyword(s): ADP-Ribosylation Factor 6 (MeSH) ; ADP-Ribosylation Factors: metabolism (MeSH) ; Actin Cytoskeleton: metabolism (MeSH) ; Animals (MeSH) ; Dendritic Spines: ultrastructure (MeSH) ; Fragile X Mental Retardation Protein: genetics (MeSH) ; Fragile X Mental Retardation Protein: metabolism (MeSH) ; Fragile X Syndrome: genetics (MeSH) ; Fragile X Syndrome: metabolism (MeSH) ; Guanine Nucleotide Exchange Factors: genetics (MeSH) ; Guanine Nucleotide Exchange Factors: metabolism (MeSH) ; Guanosine Triphosphate: metabolism (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Neuronal Plasticity: genetics (MeSH) ; Neurons: metabolism (MeSH) ; RNA Interference (MeSH) ; Receptors, Metabotropic Glutamate: metabolism (MeSH) ; Synaptosomes: metabolism (MeSH)

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Contributing Institute(s):

1. Network Dysfunction (AG Schmitz 1)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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