Sox1-deficient mice suffer from epilepsy associated with abnormal ventral forebrain development and olfactory cortex hyperexcitability.
Mutations in several classes of embryonically-expressed transcription factor genes are associated with behavioral disorders and epilepsies. However, there is little known about how such genetic and neurodevelopmental defects lead to brain dysfunction. Here we present the characterization of an epilepsy syndrome caused by the absence of the transcription factor SOX1 in mice. In vivo electroencephalographic recordings from SOX1 mutants established a correlation between behavioral changes and cortical output that was consistent with a seizure origin in the limbic forebrain. In vitro intracellular recordings from three major forebrain regions, neocortex, hippocampus and olfactory (piriform) cortex (OC) showed that only the OC exhibits abnormal enhanced synaptic excitability and spontaneous epileptiform discharges. Furthermore, the hyperexcitability of the OC neurons was present in mutants prior to the onset of seizures but was completely absent from both the hippocampus and neocortex of the same animals. The local inhibitory GABAergic neurotransmission remained normal in the OC of SOX1-deficient brains, but there was a severe developmental deficit of OC postsynaptic target neurons, mainly GABAergic projection neurons within the olfactory tubercle and the nucleus accumbens shell. Our data show that SOX1 is essential for ventral telencephalic development and suggest that the neurodevelopmental defect disrupts local neuronal circuits leading to epilepsy in the SOX1-deficient mice.
Malas
S
S
Mammalian Neurogenesis Group, MRC, Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital Campus, Du Cane Rd, London W12 0NN, UK.
Postlethwaite
M
M
Ekonomou
A
A
Whalley
B
B
Nishiguchi
S
S
Wood
H
H
Meldrum
B
B
Constanti
A
A
Episkopou
V
V
D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D016555:Matched-Pair Analysis; D008564:Membrane Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D009431:Neural Conduction; D009474:Neurons / Q000378:metabolism; D009833:Olfactory Pathways / Q000002:abnormalities*; D018408:Patch-Clamp Techniques / Q000379:methods; D016548:Prosencephalon / Q000002:abnormalities* / Q000196:embryology / Q000254:growth & development; D055748:SOXB1 Transcription Factors; D009435:Synaptic Transmission
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D055748:SOXB1 Transcription Factors; C098693:Sox1 protein, mouse