Homozygous deletion of the LGI1 gene in mice leads to developmental abnormalities resulting in cortical dysplasia

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11 Citations (Scopus)

Abstract

LGI1 mutations lead to an autosomal dominant form of epilepsy. Lgi1 mutant null mice develop seizures and show abnormal neuronal excitability. A fine structure analysis of the cortex in these mice demonstrated a subtle cortical dysplasia, preferentially affecting layers II-IV, associated with increased Foxp2 and Cux1-expressing neurons leading to blurring of the cortical layers. The hypercellularity observed in the null cortex resulted from an admixture of highly branched mature pyramidal neurons with short and poorly aligned axons as revealed by Golgi staining and immature small neurons with branched disoriented dendrites with reduced spine density and undersized, morphologically altered and round-headed spines. In vitro, hippocampal neurons revealed poor neurite outgrowth in null mice as well as reduced synapse formation. Electron microscopy demonstrated reduced spine-localized asymmetric (axospinous) synapses with postsynaptic densities and vesicle-loaded synapses in the mutant null cortex. The overall pathology in the null mice suggested cortical dyslamination most likely because of mislocalization of late-born neurons, with an admixture of those carrying suboptimally developed axons and dendrites with reduced functional synapses with normal neurons. Our study suggests that LGI1 has a role in regulating cortical development, which is increasingly becoming recognized as one of the causes of idiopathic epilepsy.

Original languageEnglish (US)
Pages (from-to)587-597
Number of pages11
JournalBrain Pathology
Volume25
Issue number5
DOIs
StatePublished - Sep 1 2015

Fingerprint

Malformations of Cortical Development
Gene Deletion
Synapses
Neurons
Spine
Dendrites
Axons
Epilepsy
Post-Synaptic Density
Pyramidal Cells
Electron Microscopy
Seizures
Pathology
Staining and Labeling
Mutation

Keywords

  • LGI1
  • cortical dysplasia
  • mouse model
  • neurite outgrowth

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

Cite this

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title = "Homozygous deletion of the LGI1 gene in mice leads to developmental abnormalities resulting in cortical dysplasia",
abstract = "LGI1 mutations lead to an autosomal dominant form of epilepsy. Lgi1 mutant null mice develop seizures and show abnormal neuronal excitability. A fine structure analysis of the cortex in these mice demonstrated a subtle cortical dysplasia, preferentially affecting layers II-IV, associated with increased Foxp2 and Cux1-expressing neurons leading to blurring of the cortical layers. The hypercellularity observed in the null cortex resulted from an admixture of highly branched mature pyramidal neurons with short and poorly aligned axons as revealed by Golgi staining and immature small neurons with branched disoriented dendrites with reduced spine density and undersized, morphologically altered and round-headed spines. In vitro, hippocampal neurons revealed poor neurite outgrowth in null mice as well as reduced synapse formation. Electron microscopy demonstrated reduced spine-localized asymmetric (axospinous) synapses with postsynaptic densities and vesicle-loaded synapses in the mutant null cortex. The overall pathology in the null mice suggested cortical dyslamination most likely because of mislocalization of late-born neurons, with an admixture of those carrying suboptimally developed axons and dendrites with reduced functional synapses with normal neurons. Our study suggests that LGI1 has a role in regulating cortical development, which is increasingly becoming recognized as one of the causes of idiopathic epilepsy.",
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AB - LGI1 mutations lead to an autosomal dominant form of epilepsy. Lgi1 mutant null mice develop seizures and show abnormal neuronal excitability. A fine structure analysis of the cortex in these mice demonstrated a subtle cortical dysplasia, preferentially affecting layers II-IV, associated with increased Foxp2 and Cux1-expressing neurons leading to blurring of the cortical layers. The hypercellularity observed in the null cortex resulted from an admixture of highly branched mature pyramidal neurons with short and poorly aligned axons as revealed by Golgi staining and immature small neurons with branched disoriented dendrites with reduced spine density and undersized, morphologically altered and round-headed spines. In vitro, hippocampal neurons revealed poor neurite outgrowth in null mice as well as reduced synapse formation. Electron microscopy demonstrated reduced spine-localized asymmetric (axospinous) synapses with postsynaptic densities and vesicle-loaded synapses in the mutant null cortex. The overall pathology in the null mice suggested cortical dyslamination most likely because of mislocalization of late-born neurons, with an admixture of those carrying suboptimally developed axons and dendrites with reduced functional synapses with normal neurons. Our study suggests that LGI1 has a role in regulating cortical development, which is increasingly becoming recognized as one of the causes of idiopathic epilepsy.

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