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突触类型特异性蛋白质组学剖析鉴定 IgSF8 为海马 CA3 微电路组织者。

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer.

机构信息

VIB Center for Brain & Disease Research, Herestraat 49, 3000, Leuven, Belgium.

KU Leuven, Department of Neurosciences, Leuven Brain Institute, Herestraat 49, 3000, Leuven, Belgium.

出版信息

Nat Commun. 2020 Oct 14;11(1):5171. doi: 10.1038/s41467-020-18956-x.

DOI:10.1038/s41467-020-18956-x
PMID:33057002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7560607/
Abstract

Excitatory and inhibitory neurons are connected into microcircuits that generate circuit output. Central in the hippocampal CA3 microcircuit is the mossy fiber (MF) synapse, which provides powerful direct excitatory input and indirect feedforward inhibition to CA3 pyramidal neurons. Here, we dissect its cell-surface protein (CSP) composition to discover novel regulators of MF synaptic connectivity. Proteomic profiling of isolated MF synaptosomes uncovers a rich CSP composition, including many CSPs without synaptic function and several that are uncharacterized. Cell-surface interactome screening identifies IgSF8 as a neuronal receptor enriched in the MF pathway. Presynaptic Igsf8 deletion impairs MF synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition. Consequently, IgSF8 loss impairs excitation/inhibition balance and increases excitability of CA3 pyramidal neurons. Our results provide insight into the CSP landscape and interactome of a specific excitatory synapse and reveal IgSF8 as a critical regulator of CA3 microcircuit connectivity and function.

摘要

兴奋性神经元和抑制性神经元连接形成微电路，产生电路输出。在海马 CA3 微电路中，中央是苔藓纤维（MF）突触，它为 CA3 锥体神经元提供强大的直接兴奋性输入和间接前馈抑制。在这里，我们剖析其细胞表面蛋白（CSP）组成，以发现 MF 突触连接的新型调节剂。分离的 MF 突触小体的蛋白质组学分析揭示了丰富的 CSP 组成，包括许多没有突触功能的 CSP 和一些未被表征的 CSP。细胞表面相互作用组筛选鉴定出 IgSF8 作为富含 MF 途径的神经元受体。突触前 IgSF8 缺失会损害 MF 突触结构，并显著降低提供前馈抑制的末梢丝状伪足的密度。因此，IgSF8 的缺失会损害兴奋/抑制平衡并增加 CA3 锥体神经元的兴奋性。我们的研究结果深入了解了特定兴奋性突触的 CSP 图谱和相互作用组，并揭示了 IgSF8 作为 CA3 微电路连接和功能的关键调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc14/7560607/fdac7407b7e0/41467_2020_18956_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc14/7560607/fdac7407b7e0/41467_2020_18956_Fig7_HTML.jpg
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