Potential conflict of interest: Nothing to report.
Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice†
Version of Record online: 22 JUN 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 66, Issue 5, pages 644–653, November 2009
How to Cite
Greenwood, J. S.F., Wang, Y., Estrada, R. C., Ackerman, L., Ohara, P. T. and Baraban, S. C. (2009), Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice. Ann Neurol., 66: 644–653. doi: 10.1002/ana.21775
- Issue online: 24 NOV 2009
- Version of Record online: 22 JUN 2009
- Accepted manuscript online: 22 JUN 2009 12:00AM EST
- Manuscript Accepted: 29 MAY 2009
- Manuscript Revised: 13 MAY 2009
- Manuscript Received: 10 DEC 2008
- Predoctoral fellowship from the Epilepsy Foundation of America
- National Institutes of Health. Grant Number: R01 NS40272
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.
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.
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.
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. Ann Neurol 2009;66:644–653