Mechanisms underlying epileptogenesis in cortical malformations.
The presence of developmental cortical malformations is associated with epileptogenesis and other neurological disorders. In recent years, animal models specific to certain malformations have been developed to study the underlying epileptogenic mechanisms. Teratogens (chemical, thermal or radiation) applied during cortical neuroblast division and migration result in lissencephaly and focal cortical dysplasia. Animals with these malformations have a lowered seizure threshold as well as histopathologies typical of those found in human dysgenic brains. Alterations that may promote epileptogenesis have been identified in lissencephalic brains, such as increased numbers of bursting types of neurons, and abnormal connections between hippocampus, subcortical heterotopia, and neocortex. A distinct set of pathological properties is present in animal models of 4-layered microgyria, induced with cortical lesions made during late stages of cortical neuroblast migration. Hyperexcitability has been demonstrated in cortex adjacent to the microgyrus (paramicrogyral zone) in in vitro slice preparations. A number of observations suggest that cellular differentiation is delayed in microgyric brains. Other studies show increases in postsynaptic glutamate receptors and decreases in GABA(A) receptors in microgyric cortex. These alterations could promote epileptogenesis, depending on which cell types have the altered receptors. The microgyrus lacks thalamic afferents from sensory relay nuclei, that instead appear to project to the paramicrogyral region, thereby increasing excitatory connectivity within this epileptogenic zone. These studies have provided a necessary first step in understanding molecular and cellular mechanisms of epileptogenesis associated with cortical malformations.
Jacobs
K M
KM
Department of Neurology and Neurological Sciences, Stanford University Medical Center, CA 94305, USA.
Kharazia
V N
VN
Prince
D A
DA
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000196:embryology* / Q000235:genetics; D006801:Humans; D008746:Methylazoxymethanol Acetate; D019384:Nucleic Acid Synthesis Inhibitors; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D019384:Nucleic Acid Synthesis Inhibitors; D008746:Methylazoxymethanol Acetate