Porter Neuroscience Research Centre, Rm3C903, Lincoln Drive, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA.
Sci Rep. 2019 Apr 1;9(1):5435. doi: 10.1038/s41598-019-41920-9.
In the hippocampal CA1, caudal ganglionic eminence (CGE)-derived interneurons are recruited by activation of glutamatergic synapses comprising GluA2-containing calcium-impermeable AMPARs and exert inhibitory regulation of the local microcircuit. However, the role played by AMPARs in maturation of the developing circuit is unknown. We demonstrate that elimination of the GluA2 subunit (GluA2 KO) of AMPARs in CGE-derived interneurons, reduces spontaneous EPSC frequency coupled to a reduction in dendritic glutamatergic synapse density. Removal of GluA1&2&3 subunits (GluA1-3 KO) in CGE-derived interneurons, almost completely eliminated sEPSCs without further reducing synapse density, but increased dendritic branching. Moreover, in GluA1-3 KOs, the number of interneurons invading the hippocampus increased in the early postnatal period but converged with WT numbers later due to increased apoptosis. However, the CCK-containing subgroup increased in number, whereas the VIP-containing subgroup decreased. Both feedforward and feedback inhibitory input onto pyramidal neurons was decreased in GluA1-3 KO. These combined anatomical, synaptic and circuit alterations, were accompanied with a wide range of behavioural abnormalities in GluA1-3 KO mice compared to GluA2 KO and WT. Thus, AMPAR subunits differentially contribute to numerous aspects of the development and maturation of CGE-derived interneurons and hippocampal circuitry that are essential for normal behaviour.
在海马体 CA1 区，尾状核隆起（CGE）衍生的中间神经元通过兴奋性突触后电流（EPSC）的激活被募集，这些兴奋性突触后电流由包含 GluA2 的钙不渗透型 AMPAR 组成，并对局部微电路施加抑制性调节。然而，AMPAR 在发育电路成熟中的作用尚不清楚。我们证明，在 CGE 衍生的中间神经元中消除 AMPAR 的 GluA2 亚基（GluA2 KO），会降低与树突状谷氨酸能突触密度降低相关的自发 EPSC 频率。在 CGE 衍生的中间神经元中消除 GluA1&2&3 亚基（GluA1-3 KO），几乎完全消除 sEPSC，而不会进一步降低突触密度，但会增加树突分支。此外，在 GluA1-3 KOs 中，在早期出生后期间，入侵海马体的中间神经元数量增加，但由于凋亡增加，后来与 WT 数量趋同。然而，CCK 含量的亚组数量增加，而 VIP 含量的亚组数量减少。在 GluA1-3 KO 中，锥体神经元的前馈和反馈抑制性输入均减少。与 GluA2 KO 和 WT 相比，GluA1-3 KO 小鼠的这些联合的解剖、突触和电路改变伴随着广泛的行为异常。因此，AMPAR 亚基对 CGE 衍生的中间神经元和海马电路的发育和成熟的许多方面做出了不同的贡献，这些方面对正常行为是必不可少的。
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