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doi: 10.1038/srep38108.

Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis

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Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis

Hongyan Zhu et al. Sci Rep..

Abstract

Voltage-gated sodium channels (VGSCs) play a vital role in controlling neuronal excitability. Nav1.6 is the most abundantly expressed VGSCs subtype in the adult central nervous system and has been found to contribute to facilitate the hyperexcitability of neurons after electrical induction of status epilepticus (SE). To clarify the exact expression patterns of Nav1.6 during epileptogenesis, we examined the expression of Nav1.6 at protein and mRNA levels in two distinct animal models of temporal lobe epilepsy (TLE) including a post-SE model induced by kainic acid (KA) intrahippocampal injection and a kindling model evoked by pentylenetetrazole (PTZ). A prominent, seizure intensity-dependent increase of Nav1.6 expression in reactive astrocytes was observed in ipsilateral hippocampus of post-SE rats, reaching the peak at 21 days after SE, a time point during the latent stage of epileptogenesis. However, Nav1.6 with low expression level was selectively expressed in the hippocampal neurons rather than astrocytes in PTZ-kindled animals. This seizure-related increase of a VGSCs subtype in reactive astrocytes after SE may represent a new mechanism for signal communication between neuron and glia in the course of epileptogenesis, facilitating the neuronal hyperexcitability.

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Figures

Figure 1
Figure 1. Real-time quantitative PCR analysis for Nav1.6 expression in the hippocampus in KA-induced post-SE rats and the control groups.
Each column represents mean ± SEM of five animals in each group. *P < 0.05, **P < 0.01, significantly different from the control animals.
Figure 2
Figure 2. Photomicrographs of Nav1.6 immunoreactivity in the hippocampus in KA-induced TLE rats and the control groups.
(A–F) Nav1.6-ir (red) is progressively increased in the ipsilateral hippocampus at 1 day, 7 days, 21 days, 63 days after SE, peaking at 21 days after SE compared with the contralateral side and the controls. (G) Nav1.6-ir (red) positive cells present morphological changes with the development of epilepsy. SO: stratum oriens; SR: stratum radiatum; SL: stratum lucidum; SP: stratum pyramidale.
Figure 3
Figure 3. Stereological analysis of Nav1.6-ir positive cell numbers in the hippocampus in KA-induced TLE rats.
There are significant increases in the number of Nav1.6-ir positive cells in the CA1 (A), CA3 (B) and hilus (C) subregions of the ipsilateral hippocampus at 1 day, 7 days, 21 days, and 63 days after SE in KA-induced TLE rats in comparison with that of the control group and the contralateral side. *P < 0.05, **P < 0.01, significantly different from the control animals.
Figure 4
Figure 4
Topographical expression of Nav1.6 in the CA1 (A), CA3 (B) and hilus (C) subregions of the ipsilateral hippocampus (from 2.4 to 5.6 mm from bregma along the rostro-caudal axis) in KA-induced TLE rats at 21 days after SE. Note that there are more Nav1.6-ir positive cells in the sections near the KA injection site (4.0 mm caudal to bregma). Data are plotted as mean ± SEM of five animals in each group. *P < 0.05, **P < 0.01, significantly different from the control animals.
Figure 5
Figure 5
(A) The number of Nav1.6-ir positive cells in the ipsilateral hippocampus was closely correlated with the onset of SE in rats with KA intrahippocampal injection (R2 = 0.754,P < 0.01). (B) Regression analysis demonstrating the strong relationship between the number of Nav1.6-ir positive cells in the ipsilateral hippocampus and the severity of SE estimated by the number of stage 5 seizures for rats experiencing SE at 7 days, 21 days and 63 days after SE (at 7 days after SE, R2 = 0.975 P < 0.01; at 21 days after SE, R2 = 0.986,p < 0.01; at 63 days after SE, R2 = 0.941,P < 0.01). (C) The number of Nav1.6-ir positive cells in the ipsilateral hippocampus was profoundly correlated with the severity of astrogliosis in post-SE rats (R2 = 0.899).
Figure 6
Figure 6. Colocalization of Nav1.6 (red) with GFAP (green) in the hippocampus in KA induced TLE rats.
(A,B) Rare Nav1.6 is colocalized with the astrocytic marker GFAP in the CA1 and CA3 subregions in the hippocampus in the controls. (C,D) Nav1.6 is highly colocalized with the astrocytic marker GFAP in the CA1 and CA3 subregions in the ipsilateral hippocampus at 21 days after-SE in KA induced TLE rats. (E,F) Note Nav1.6-ir is extensively distributed in the soma and process of GFAP-ir positive cells in the ipsilateral hippocampus at 21 days after-SE in KA induced TLE rats at high magnification. The colocalization ratios of Nav1.6 with GFAP in the hippocampal CA1 and CA3 subregions in KA induced TLE rats and the controls are shown in (G,H). Data are plotted as mean ± SEM of five animals in each group. SO: stratum oriens; SR: stratum radiatum; SL: stratum lucidum; SP: stratum pyramidale. *P < 0.05, **P < 0.01, significantly different from control animals.
Figure 7
Figure 7. Colocalization of Nav1.6 (red) with nestin (green) in the hippocampus in KA induced TLE rats.
(A,B) Rare Nav1.6 is colocalized with nestin in the CA1 and CA3 subregions in the hippocampus in the controls. (C,D) Nav1.6 is highly colocalized with nestin in the CA1 and CA3 subregions in the ipsilateral hippocampus at 21 days after-SE in KA induced TLE rats. (E,F) Note Nav1.6-ir is extensively distributed in the soma and process of nestin-ir positive cells in the ipsilateral hippocampus at 21 days after-SE in KA induced TLE rats at high magnification. The colocalization ratios of Nav1.6 with nestin in the hippocampal CA1 and CA3 subregions in KA induced TLE rats and the controls are shown inG andH. Data are plotted as mean ± SEM of five animals in each group. SO: stratum oriens; SR: stratum radiatum; SL: stratum lucidum; SP: stratum pyramidale. *P < 0.05, **P < 0.01, significantly different from the control animals.
Figure 8
Figure 8. Colocalization of Nav1.6 (red) with NeuN, MAP2, O4, OX-42 or Ankyrin G (green) in the CA3 subarea of the ipsilateral hippocampus at 21 days after-SE in KA induced TLE rats.
Nav1.6 is seldom co-expressed with the neuronal marker NeuN (A) or MAP2 (C), oligodendrocyte marker O4 (B), and microglia marker OX42 (D). A small amount of Nav1.6 is co-localized with Ankyrin G (E–H).
Figure 9
Figure 9. Expression of Nav1.6 in the hippocampus in PTZ-kindled animals.
(A) Real-time PCR analysis for Nav1.6 expression in the hippocampus in PTZ-kindled animals and the control groups. Each column represents mean ± SEM of five animals in each group. *P < 0.05, **P < 0.01, significantly different from the control animals. (B–E) A small amount of Nav1.6-ir is observed in the stratum pyramidale in the hippocampus in PTZ-kindled animals and the controls. Nav1.6-ir (red) is not co-localized with GFAP-ir positive cells (green) both in the controls and PTZ-kindled rats (B,C). Nav1.6-ir (red) is located in NeuN-ir positive cells (green) both in the controls and PTZ-kindled rats (D,E).
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