期刊
CEREBRAL CORTEX
卷 24, 期 4, 页码 1088-1101出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhs375
关键词
-aminobutyric acid; focal freeze-lesion; KCC2; microgyrus; neuronal migration
资金
- Japan Society for the Promotion of Science [19390058]
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [20021015, 21026013]
- Grants-in-Aid for Scientific Research [25293052, 20021015, 21026013, 22300113, 24659508, 23500444, 19390058, 25282164, 23500516] Funding Source: KAKEN
Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the -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 decarboxylasegreen 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 GABA(A) receptor-mediated Ca-2 oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.
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