User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse




Journal Article

The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome


Briševac,  Dušica
Max Planck Research Group Biological Clocks, Max Planck Institute for Evolutionary Biology, Max Planck Society;

External Ressource
No external resources are shared
Fulltext (public)

(Publisher version), 3MB

Supplementary Material (public)
There is no public supplementary material available

Briševac, D., Scholz, R., Du, D., Elagabani, M. N., Köhr, G., & Kornau, H.-C. (2020). The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome. Journal of Neurochemistry: official journal of the International Society for Neurochemistry, 00, 1-18. doi:10.1111/JNC.15230.

Cite as: http://hdl.handle.net/21.11116/0000-0007-9E68-3
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the Fragile X mental retardation gene 1 (FMR1). 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 Fmr1knockout 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 Fmr1knockout 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 three-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.