 |
Previous Article | Next Article 
The Journal of Neuroscience, April 1, 2000, 20(7):2439-2450
Hippocampal Abnormalities and Enhanced Excitability in a Murine
Model of Human Lissencephaly
Mark W.
Fleck1,
Shinji
Hirotsune2,
Michael J.
Gambello2,
Emily
Phillips-Tansey1,
Gregory
Suares1,
Ronald F.
Mervis3,
Anthony
Wynshaw-Boris2, and
Chris J.
McBain1
1 Laboratory of Cellular and Molecular Neurophysiology,
National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland 20892, 2 Genetic
Disease Research Branch, National Human Genome Research
Institute, National Institutes of Health, Bethesda, Maryland
20892, and 3 Neuro-Cognitive Research Labs, Columbus, Ohio
43212
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.
Key words:
lissencephaly; platelet-activating factor
acetylhydrolase; knockout mouse; hippocampus; bromodeoxyuridine; Golgi; epilepsy; potassium
Copyright © 2000 Society for Neuroscience 0270-6474/00/2072439-12$05.00/0
This article has been cited by other articles:

|
 |

|
 |
 
F.-W. Zhou, H.-X. Chen, and S. N. Roper
Balance of Inhibitory and Excitatory Synaptic Activity Is Altered in Fast-Spiking Interneurons in Experimental Cortical Dysplasia
J Neurophysiol,
October 1, 2009;
102(4):
2514 - 2525.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
V. J. Peschansky, T. J. Burbridge, A. J. Volz, C. Fiondella, Z. Wissner-Gross, A. M. Galaburda, J. J. L. Turco, and G. D. Rosen
The Effect of Variation in Expression of the Candidate Dyslexia Susceptibility Gene Homolog Kiaa0319 on Neuronal Migration and Dendritic Morphology in the Rat
Cereb Cortex,
August 13, 2009;
(2009)
bhp154v1.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. L. Jones and S. C. Baraban
Inhibitory Inputs to Hippocampal Interneurons Are Reorganized in Lis1 Mutant Mice
J Neurophysiol,
August 1, 2009;
102(2):
648 - 658.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Kerjan, H. Koizumi, E. B. Han, C. M. Dube, S. N. Djakovic, G. N. Patrick, T. Z. Baram, S. F. Heinemann, and J. G. Gleeson
Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures
PNAS,
April 21, 2009;
106(16):
6766 - 6771.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. B. Ackman, L. Aniksztejn, V. Crepel, H. Becq, C. Pellegrino, C. Cardoso, Y. Ben-Ari, and A. Represa
Abnormal Network Activity in a Targeted Genetic Model of Human Double Cortex
J. Neurosci.,
January 14, 2009;
29(2):
313 - 327.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Fallet-Bianco, L. Loeuillet, K. Poirier, P. Loget, F. Chapon, L. Pasquier, Y. Saillour, C. Beldjord, J. Chelly, and F. Francis
Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A
Brain,
September 1, 2008;
131(9):
2304 - 2320.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. L. Jones and S. C. Baraban
Characterization of Inhibitory Circuits in the Malformed Hippocampus of Lis1 Mutant Mice
J Neurophysiol,
November 1, 2007;
98(5):
2737 - 2746.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. B. Vallee and J.-W. Tsai
The cellular roles of the lissencephaly gene LIS1, and what they tell us about brain development
Genes & Dev.,
June 1, 2006;
20(11):
1384 - 1393.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J.-W. Tsai, Y. Chen, A. R. Kriegstein, and R. B. Vallee
LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages
J. Cell Biol.,
September 12, 2005;
170(6):
935 - 945.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. F. McManus and J. A. Golden
Topical Review: Neuronal Migration in Developmental Disorders
J Child Neurol,
April 1, 2005;
20(4):
280 - 286.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
M. F. McManus, I. M. Nasrallah, M. M. Pancoast, A. Wynshaw-Boris, and J. A. Golden
Lis1 Is Necessary for Normal Non-Radial Migration of Inhibitory Interneurons
Am. J. Pathol.,
September 1, 2004;
165(3):
775 - 784.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. F. McManus and J. A. Golden
Topical Review: Neuronal Migration in Developmental Disorders
J Child Neurol,
March 1, 2004;
19(3):
280 - 286.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
M. J. Gambello, D. L. Darling, J. Yingling, T. Tanaka, J. G. Gleeson, and A. Wynshaw-Boris
Multiple Dose-Dependent Effects of Lis1 on Cerebral Cortical Development
J. Neurosci.,
March 1, 2003;
23(5):
1719 - 1729.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. C. Corbo, T. A. Deuel, J. M. Long, P. LaPorte, E. Tsai, A. Wynshaw-Boris, and C. A. Walsh
Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex
J. Neurosci.,
September 1, 2002;
22(17):
7548 - 7557.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. E. Calcagnotto, M. F. Paredes, and S. C. Baraban
Heterotopic Neurons with Altered Inhibitory Synaptic Function in an Animal Model of Malformation-Associated Epilepsy
J. Neurosci.,
September 1, 2002;
22(17):
7596 - 7605.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. N. Roper and A. T. Yachnis
Book Review: Cortical Dysgenesis and Epilepsy
Neuroscientist,
August 1, 2002;
8(4):
356 - 371.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
B. E. Porter, A. Brooks-Kayal, and J. A. Golden
Disorders of Cortical Development and Epilepsy
Arch Neurol,
March 1, 2002;
59(3):
361 - 365.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Wynshaw-Boris and M. J. Gambello
LIS1 and dynein motor function in neuronal migration and development
Genes & Dev.,
March 15, 2001;
15(6):
639 - 651.
[Full Text]
|
 |
|

|
 |

|
 |
 
H. J. Wenzel, C. A. Robbins, L.-H. Tsai, and P. A. Schwartzkroin
Abnormal Morphological and Functional Organization of the Hippocampus in a p35 Mutant Model of Cortical Dysplasia Associated with Spontaneous Seizures
J. Neurosci.,
February 1, 2001;
21(3):
983 - 998.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Caspi, R. Atlas, A. Kantor, T. Sapir, and O. Reiner
Interaction between LIS1 and doublecortin, two lissencephaly gene products
Hum. Mol. Genet.,
September 1, 2000;
9(15):
2205 - 2213.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|

|