Neuronal F-Box protein FBXO41 regulates synaptic transmission and hippocampal network maturation
Ana R.A.A. Quadros,
Rocío Díez Arazola,
Andrea Romaguera Álvarez,
Johny Pires,
Rhiannon M. Meredith,
Ingrid Saarloos,
Matthijs Verhage,
Ruud F. Toonen
Affiliations
Ana R.A.A. Quadros
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Rocío Díez Arazola
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Andrea Romaguera Álvarez
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Johny Pires
Department of Integrative Neurophysiology, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Rhiannon M. Meredith
Department of Integrative Neurophysiology, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Ingrid Saarloos
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands; Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Matthijs Verhage
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands; Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Ruud F. Toonen
Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands; Corresponding author
Summary: 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.
