title: Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.
abstract: Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Tianying
authors.initials: T
authors.lastname: Wang
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kumada
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Morishima
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000473:pathology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D008297:Male; D054220:Malformations of Cortical Development / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009584:Nitrogen / Q000633:toxicity; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D001640:Bicuculline; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase; D009584:Nitrogen; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C402565:glutamate decarboxylase 1