Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice.
Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice.
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DOI：
10.1523/eneuro.0088-17.2017
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发表时间：
2017-05
期刊：
影响因子：
3.4
通讯作者：
Williams ME
中科院分区：
文献类型：
--
作者：
Martin EA;Woodruff D;Rawson RL;Williams ME
神经回路平衡兴奋性和抑制性活动，这种平衡的破坏常见于神经发育障碍。缺乏智力障碍和自闭症相关基因 Kirrel3 的小鼠的海马体存在兴奋-抑制失衡，但这种功能缺陷背后的精确突触变化尚不清楚。 Kirrel3 是一种在齿状回 (DG) 和 GABA 神经元中表达的同质粘附分子。有人提出，Kirrel3 基因敲除小鼠海马神经元的兴奋-抑制失衡是由于苔藓纤维 (MF) 丝状伪足的丧失，这种丝状伪足是 DG 轴突突起，被认为可以兴奋 GABA 神经元，从而为 CA3 锥体神经元提供前馈抑制。在 Kirrel3 敲除小鼠中观察到的丝状伪足结构较少，但既没有检查丝状伪足突触，也没有检查也刺激 GABA 神经元的 DG en passant 突触。在这里，我们使用具有 3D 重建功能的串行块面扫描电子显微镜 (SBEM) 来定义 MF 丝状伪足的精确连接性，并阐明 Kirrel3 丢失引起的突触变化。令人惊讶的是，我们发现野生型 MF 丝状伪足并不像之前认为的那样只突触到 GABA 神经元，而是以相似的频率突触到 GABA 神经元和 CA3 神经元。此外，Kirrel3 的缺失选择性地减少了 GABA 神经元上的 MF 丝状突触，但不减少 CA3 神经元或经过的突触上的 MF 丝状突触。总之，MF 丝状突触与 GABA 神经元的选择性丧失可能是在 Kirrel3 敲除小鼠中观察到的海马活动失衡的基础，并可能影响 Kirrel3 依赖性神经发育障碍患者的神经功能。
Neural circuits balance excitatory and inhibitory activity and disruptions in this balance are commonly found in neurodevelopmental disorders. Mice lacking the intellectual disability and autism-associated gene Kirrel3 have an excitation-inhibition imbalance in the hippocampus but the precise synaptic changes underlying this functional defect are unknown. Kirrel3 is a homophilic adhesion molecule expressed in dentate gyrus (DG) and GABA neurons. It was suggested that the excitation-inhibition imbalance of hippocampal neurons in Kirrel3 knockout mice is due to loss of mossy fiber (MF) filopodia, which are DG axon protrusions thought to excite GABA neurons and thereby provide feed-forward inhibition to CA3 pyramidal neurons. Fewer filopodial structures were observed in Kirrel3 knockout mice but neither filopodial synapses nor DG en passant synapses, which also excite GABA neurons, were examined. Here, we used serial block-face scanning electron microscopy (SBEM) with 3D reconstruction to define the precise connectivity of MF filopodia and elucidate synaptic changes induced by Kirrel3 loss. Surprisingly, we discovered wildtype MF filopodia do not synapse exclusively onto GABA neurons as previously thought, but instead synapse with similar frequency onto GABA neurons and CA3 neurons. Moreover, Kirrel3 loss selectively reduces MF filopodial synapses onto GABA neurons but not those made onto CA3 neurons or en passant synapses. In sum, the selective loss of MF filopodial synapses with GABA neurons likely underlies the hippocampal activity imbalance observed in Kirrel3 knockout mice and may impact neural function in patients with Kirrel3-dependent neurodevelopmental disorders.