Hippocampal Abnormalities and Enhanced Excitability in a Murine Model of Human Lissencephaly

摘要: Human cortical heterotopia and neuronal migration disorders result in epilepsy; however, the precise mechanisms remain elusive. Here we demonstrate severe dysplasia throughout granule cell pyramidal layers of mice containing a heterozygous deletion Lis1, mouse model human 17p13.3-linked lissencephaly. Birth-dating analysis using bromodeoxyuridine revealed that neurons Lis1+/- murine hippocampus are born at appropriate time but fail to form defined layer. Heterotopic were stunted possessed fewer dendritic branches, whereas dentate cells hypertrophic formed spiny basilar dendrites from which principal axon emerged. Both somatostatin- parvalbumin-containing inhibitory heterotopic displaced into both stratum radiatum lacunosum-moleculare. Mechanisms synaptic transmission severely disrupted, revealing hyperexcitability Schaffer collateral-CA1 synapses depression mossy fiber-CA3 transmission. In addition, dynamic range frequency-dependent facilitation fiber was less than wild type. Consequently, hippocampi prone interictal electrographic seizure activity an elevated [K(+)](o) epilepsy. hippocampus, intense bursting observed on elevation extracellular potassium 6.5 mM, condition resulted only minimal These anatomical physiological hippocampal defects may provide basis for seizures associated with