Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.
OBJECTIVE
In humans, abnormal neuronal migration and severe neuronal disorganization resulting from Lis1 (lissencephaly) haploinsufficiency contributes to cognitive impairment and seizures early in life. In Lis1 heterozygotic mice, severe hippocampal disorganization and cognitive impairment have also been reported. Using this mouse model, we examined the functional impact of LIS1 deficiency with particular focus on excitatory glutamate-mediated synaptic transmission.


METHODS
We used visualized patch-clamp recordings in acute hippocampal slices. We recorded spontaneous, miniature and stimulation-evoked excitatory postsynaptic current (EPSC). Additional mice were processed for immunohistochemistry, electron microscopy (EM), or video-electroencephalographic (EEG) monitoring.


RESULTS
Video-EEG confirmed the presence of spontaneous electrographic seizures in Lis1 mutant mice. In disorganized hippocampal slices from Lis1(+/-) mice, we noted a nearly two-fold significant increase in the frequency of spontaneous and miniature EPSC; no significant change in amplitude or decay was noted. Synaptic function assessed using brief repetitive or paired-pulse stimulation protocols, also revealed significant enhancement of glutamate-mediated excitation. Low concentrations of cadmium, a nonspecific blocker of voltage-dependent calcium channels mediating vesicle release, effectively restored paired-pulse facilitation deficits back to control levels. Analysis of synapse ultrastructure at the EM level identified a large increase in synaptic vesicle number.


CONCLUSIONS
Seizure activity, possibly associated with increased glutamate-mediated excitation and an increased pool of vesicles at the presynaptic site, was demonstrated in a mouse model of type I lissencephaly.
Greenwood
Joel S F
JS
Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA.
Wang
Yanling
Y
Estrada
Rosanne C
RC
Ackerman
Larry
L
Ohara
Peter T
PT
Baraban
Scott C
SC
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D000818:Animals; D002452:Cell Count / Q000379:methods; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D013572:Synaptic Vesicles / Q000235:genetics* / Q000473:pathology
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse