Hippocampal abnormalities and enhanced excitability in a murine model of human lissencephaly.
Human cortical heterotopia and neuronal migration disorders result in epilepsy; however, the precise mechanisms remain elusive. Here we demonstrate severe neuronal dysplasia and heterotopia throughout the granule cell and pyramidal cell layers of mice containing a heterozygous deletion of Lis1, a mouse model of human 17p13.3-linked lissencephaly. Birth-dating analysis using bromodeoxyuridine revealed that neurons in Lis1+/- murine hippocampus are born at the appropriate time but fail in migration to form a defined cell layer. Heterotopic pyramidal neurons in Lis1+/- mice were stunted and possessed fewer dendritic branches, whereas dentate granule cells were hypertrophic and formed spiny basilar dendrites from which the principal axon emerged. Both somatostatin- and parvalbumin-containing inhibitory neurons were heterotopic and displaced into both stratum radiatum and stratum lacunosum-moleculare. Mechanisms of synaptic transmission were severely disrupted, revealing hyperexcitability at Schaffer collateral-CA1 synapses and depression of mossy fiber-CA3 transmission. In addition, the dynamic range of frequency-dependent facilitation of Lis1+/- mossy fiber transmission was less than that of wild type. Consequently, Lis1+/- hippocampi are prone to interictal electrographic seizure activity in an elevated [K(+)](o) model of epilepsy. In Lis1+/- hippocampus, intense interictal bursting was observed on elevation of extracellular potassium to 6.5 mM, a condition that resulted in only minimal bursting in wild type. These anatomical and physiological hippocampal defects may provide a neuronal basis for seizures associated with lissencephaly.
Fleck
M W
MW
Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hirotsune
S
S
Gambello
M J
MJ
Phillips-Tansey
E
E
Suares
G
G
Mervis
R F
RF
Wynshaw-Boris
A
A
McBain
C J
CJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002465:Cell Movement; D002828:Choristoma / Q000473:pathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology*; D006056:Golgi Apparatus / Q000648:ultrastructure; D006624:Hippocampus / Q000002:abnormalities*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009421:Nervous System Malformations / Q000473:pathology*; D009474:Neurons / Q000502:physiology; D010320:Parvalbumins / Q000032:analysis; D013004:Somatostatin / Q000032:analysis
D008869:Microtubule-Associated Proteins; D010320:Parvalbumins; D013004:Somatostatin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse; D001973:Bromodeoxyuridine