Neuroscience Graduate Program, Oregon Health & Science University, Portland, OR, 97239, USA.
Vollum Institute, Oregon Health & Science University, VIB 3435A, 3181 SW Sam Jackson Park Road, L474, Portland, OR, 97239-3098, USA.
Neural Dev. 2021 Aug 6;16(1):4. doi: 10.1186/s13064-021-00153-1.
The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to initially recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. However, the precise temporal requirement for Dystroglycan during inhibitory synapse development has not been examined.
In this study, we use NEX or Camk2a to conditionally delete Dystroglycan from newly-born or adult pyramidal neurons, respectively. We then analyze forebrain development from postnatal day 3 through adulthood, with a particular focus on CCK+ interneurons.
In the absence of postsynaptic Dystroglycan in developing pyramidal neurons, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb during the first two postnatal weeks. Other interneuron subtypes are unaffected, indicating that CCK+ interneurons are unique in their requirement for postsynaptic Dystroglycan. Dystroglycan does not appear to be required in adult pyramidal neurons to maintain CCK+ interneurons. Bax deletion did not rescue CCK+ interneurons in Dystroglycan mutants during development, suggesting that they are not eliminated by canonical apoptosis. Rather, we observed increased innervation of the striatum, suggesting that the few remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact.
Together these findings show that Dystroglycan functions as part of a synaptic partner recognition complex that is required early for CCK+ interneuron development in the forebrain.
功能性神经回路的发育需要不同神经元群体之间精确形成突触连接。在哺乳动物大脑中，允许 GABA 能中间神经元亚型最初识别其突触后靶标的分子途径在很大程度上仍然未知。跨膜糖蛋白 Dystroglycan 定位于锥体神经元中的抑制性突触，在那里它是 CCK+中间神经元正常功能所必需的。然而，Dystroglycan 在抑制性突触发育过程中的精确时间要求尚未被研究。
在这项研究中，我们分别使用 NEX 或 Camk2a 条件性地从新生或成年锥体神经元中删除 Dystroglycan。然后，我们分析了从出生后第 3 天到成年期的前脑发育，特别关注 CCK+中间神经元。
在发育中的锥体神经元中缺乏突触后 Dystroglycan 时，CCK+中间神经元未能发育其轴突，并在出生后前两周内从大脑皮层、海马体、杏仁核和嗅球中大量消失。其他中间神经元亚型不受影响，表明 CCK+中间神经元在其对突触后 Dystroglycan 的需求上是独特的。Dystroglycan 在成年锥体神经元中似乎不需要维持 CCK+中间神经元。在发育过程中，Bax 缺失未能挽救 Dystroglycan 突变体中的 CCK+中间神经元，这表明它们不是通过经典凋亡消除的。相反，我们观察到纹状体的神经支配增加，表明少数剩余的 CCK+中间神经元重新定向其轴突到邻近的区域，那里的 Dystroglycan 表达仍然完整。
这些发现表明 Dystroglycan 作为突触伙伴识别复合物的一部分发挥作用，该复合物在大脑前脑的 CCK+中间神经元发育早期是必需的。
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