Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility
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DOI：
10.3727/096368910x491383
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发表时间：
2010-05
影响因子：
3.3
通讯作者：
I. Zipancic;M. E. Calcagnotto;Marina Piquer‐Gil;Luiz E. Mello;M. Álvarez-Dolado
中科院分区：
文献类型：
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作者：
I. Zipancic;M. E. Calcagnotto;Marina Piquer‐Gil;Luiz E. Mello;M. Álvarez-Dolado
GABA能功能缺陷可导致癫痫。在过去的几年里，基于细胞的疗法试图纠正这些缺陷，在癫痫动物模型上取得了不同的成功。最近，我们证明了内侧神经节隆起（MGE）来源的细胞移植到新生儿正常脑迁移和分化为功能成熟的GABA能中间神经元。这些细胞能够调节GABA介导的突触抑制的局部水平，这表明它们适用于基于细胞的疗法。然而，目前尚不清楚它们是否可以整合到宿主电路中并挽救病理条件下的抑制丧失。因此，作为原理的证明，我们将MGE衍生的细胞移植到癫痫发作易感性的小鼠模型中，所述癫痫发作易感性是在注射与P物质缀合的神经毒性皂草素（SSP-Sap）后通过特异性消除小鼠海马中的GABA能中间神经元亚群引起的。这种消融与CA 1锥体细胞上抑制性突触后电流（IPSC）的显著减少和戊四氮（PTZ）诱导的癫痫发作易感性增加有关。GFP+ MGE衍生的细胞在SSP-Sap处理的小鼠中的移植用表达成熟中间神经元的分子标记物的细胞重新填充海马消融区。有趣的是，IPSC对消融海马CA 1锥体细胞的动力学在移植后显著增加，达到与正常小鼠相似的水平。更重要的是，这与癫痫发作严重程度的降低和PTZ诱导的癫痫发作后死亡率的降低有关。我们的数据表明，MGE衍生的细胞满足了适当的基于细胞的治疗的大部分要求，并表明它们适用于需要调节突触抑制的神经系统疾病，如癫痫。
Defects in GABAergic function can cause epilepsy. In the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP+ MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.