TY - JOUR
T1 - Neuronal F-Box protein FBXO41 regulates synaptic transmission and hippocampal network maturation
AU - Quadros, Ana R.A.A.
AU - Arazola, Rocío Díez
AU - Álvarez, Andrea Romaguera
AU - Pires, Johny
AU - Meredith, Rhiannon M.
AU - Saarloos, Ingrid
AU - Verhage, Matthijs
AU - Toonen, Ruud F.
N1 - Funding Information: We thank Robbert Zalm, Joost Hoetjes, and Frank Den Oudsten for genotyping, Desiree Schut and Lisa Laan for culturing glia and primary culture assistance, Joke Wortel for help with slice staining and mouse colony handling, Jurjen Broeke for technical assistance, and other members of the Toonen lab for helpful discussions. We thank Dr J. Stegmueller for Fbxo41 breeding pairs. This work was supported by the Netherlands Organisation for Scientific Research (ZonMW-TOP 91208017 to R.F.T.; ZonMW 903-42-095 to MV) and by the EU (Neuron Cofund ERA-Net SNAREopathy to R.F.T., and CognitionNet FP7-ITN-607508 to A.R.A.A.Q.). Publisher Copyright: © 2022 The Author(s)
PY - 2022/4/15
Y1 - 2022/4/15
N2 - FBXO41 is a neuron-specific E3 ligase subunit implicated in epileptic encephalopathies. Fbxo41 null mutant (KO) mice show behavioral deficits and early lethality. Here, we report that loss of FBXO41 causes defects in synaptic transmission and brain development. Cultured Fbxo41 KO neurons had normal morphology and showed no signs of degeneration. Single-cell electrophysiology showed a lower synaptic vesicle release probability in excitatory neurons. Inhibitory neurons exhibited reduced synaptophysin expression, a smaller readily releasable pool, and decreased charge transfer during repetitive stimulation. In Fbxo41 KO hippocampal slices at postnatal day 6, the dentate gyrus was smaller with fewer radial-glial-like cells and immature neurons. In addition, neuronal migration was delayed. Two-photon calcium imaging showed a delayed increase in network activity and synchronicity. Together, our findings point toward a role for FBXO41 in synaptic transmission and postnatal brain development, before behavioral deficits are detected in Fbxo41 KO mice.
AB - FBXO41 is a neuron-specific E3 ligase subunit implicated in epileptic encephalopathies. Fbxo41 null mutant (KO) mice show behavioral deficits and early lethality. Here, we report that loss of FBXO41 causes defects in synaptic transmission and brain development. Cultured Fbxo41 KO neurons had normal morphology and showed no signs of degeneration. Single-cell electrophysiology showed a lower synaptic vesicle release probability in excitatory neurons. Inhibitory neurons exhibited reduced synaptophysin expression, a smaller readily releasable pool, and decreased charge transfer during repetitive stimulation. In Fbxo41 KO hippocampal slices at postnatal day 6, the dentate gyrus was smaller with fewer radial-glial-like cells and immature neurons. In addition, neuronal migration was delayed. Two-photon calcium imaging showed a delayed increase in network activity and synchronicity. Together, our findings point toward a role for FBXO41 in synaptic transmission and postnatal brain development, before behavioral deficits are detected in Fbxo41 KO mice.
KW - Cellular neuroscience
KW - Developmental neuroscience
KW - Molecular neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85127211270&partnerID=8YFLogxK
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U2 - https://doi.org/10.1016/j.isci.2022.104069
DO - https://doi.org/10.1016/j.isci.2022.104069
M3 - Article
C2 - 35372812
SN - 2589-0042
VL - 25
SP - 1
EP - 18
JO - iScience
JF - iScience
IS - 4
M1 - 104069
ER -