Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b-null mice and precedes hyperexcitability
Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b-null mice and precedes hyperexcitability
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DOI：
10.1073/pnas.1208767110
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发表时间：
2013-01-15
影响因子：
11.1
通讯作者：
Isom, Lori L.
中科院分区：
文献类型：
--
作者：
Brackenbury, William J.;Yuan, Yukun;Isom, Lori L.
电压门控 Na+ 通道 (VGSC) beta 1 亚基由 SCN1B 编码，是多功能通道调节剂和细胞粘附分子 (CAM)。 SCN1B 突变与人类遗传性癫痫伴热性惊厥附加 (GEFS+) 谱系障碍相关，Scn1b 缺失小鼠从出生后第 10 天 (P) 起表现出严重的自发性癫痫发作和共济失调。本研究的目的是确定 Scn1b 缺失小鼠出生后早期大脑发育过程中神经元寻路的变化，以检验 Scn1b 的这些 CAM 介导的作用可能有助于过度兴奋性发展的假设。 c-Fos 是一种响应癫痫活动而诱导的蛋白质，在 Scn1b 缺失的大脑中在 P16 时上调，但在 P5 时没有上调。与此一致的是，在 P16 而非 P5-P7 Scn1b 缺失大脑制备的海马和皮质切片中观察到癫痫样活动。根据这些结果，我们研究了 P5 的神经元寻路。我们观察到 P5 无效小脑中平行纤维的束颤被破坏。此外，P5缺失小鼠表现出齿状回颗粒细胞层中神经元密度降低、门中颗粒细胞前体增殖增加、以及齿状回和CA1中的轴突延伸缺陷和胞体以及抑制性神经元突起的定向错误。因此，Scn1b 在大脑发育的关键出生后时期对于神经元增殖、迁移和寻路至关重要。我们认为，Scn1b 缺失导致的神经元增殖、迁移和寻路缺陷可能导致过度兴奋的发生。
Voltage-gated Na+ channel (VGSC) beta 1 subunits, encoded by SCN1B, are multifunctional channel modulators and cell adhesion molecules (CAMs). Mutations in SCN1B are associated with the genetic epilepsy with febrile seizures plus (GEFS+) spectrum disorders in humans, and Scn1b-null mice display severe spontaneous seizures and ataxia from postnatal day (P) 10. The goal of this study was to determine changes in neuronal pathfinding during early postnatal brain development of Scn1b-null mice to test the hypothesis that these CAM-mediated roles of Scn1b may contribute to the development of hyperexcitability. c-Fos, a protein induced in response to seizure activity, was up-regulated in the Scn1b-null brain at P16 but not at P5. Consistent with this, epileptiform activity was observed in hippocampal and cortical slices prepared from the P16 but not from the P5-P7 Scn1b-null brain. On the basis of these results, we investigated neuronal pathfinding at P5. We observed disrupted fasciculation of parallel fibers in the P5 null cerebellum. Further, P5 null mice showed reduced neuron density in the dentate gyrus granule cell layer, increased proliferation of granule cell precursors in the hilus, and defective axonal extension and misorientation of somata and processes of inhibitory neurons in the dentate gyrus and CA1. Thus, Scn1b is critical for neuronal proliferation, migration, and pathfinding during the critical postnatal period of brain development. We propose that defective neuronal proliferation, migration, and pathfinding in response to Scn1b deletion may contribute to the development of hyperexcitability.