Carroll Julianne B, Hamidi Shaida, Gabriele Mark L
Department of Biology, James Madison University, Harrisonburg, VA, United States.
Front Neurosci. 2023 Jan 4;16:1072667. doi: 10.3389/fnins.2022.1072667. eCollection 2022.
The lateral cortex of the inferior colliculus (LCIC) is a midbrain shell region that receives multimodal inputs that target discrete zones of its compartmental (modular-matrix) framework. This arrangement emerges perinatally in mice (postnatal day, P0-P12) as somatosensory and auditory inputs segregate into their respective modular and matrix terminal patterns. Microglial cells (MGCs) perform a variety of critical functions in the developing brain, among them identifying areas of active circuit assembly and selectively pruning exuberant or underutilized connections. Recent evidence in other brain structures suggest considerable MGC heterogeneity across the lifespan, particularly during established developmental critical periods. The present study examines the potential involvement of classical complement cascade signaling (C3-CR3/CD11b) in refining early multisensory networks, and identifies several microglial subsets exhibiting distinct molecular signatures within the nascent LCIC. Immunostaining was performed in GAD67-green fluorescent protein (GFP) and CX3CR1-GFP mice throughout and after the defined LCIC critical period. GAD labeling highlights the emerging LCIC modularity, while CX3CR1 labeling depicts MGCs expressing the fractalkine receptor. C3 expression is widespread throughout the LCIC neuropil early on, prior to its conspicuous absence from modular zones at P8, and more global disappearance following critical period closure. CD11b-expressing microglia while homogeneously distributed at birth, are biased to modular fields at P8 and then the surrounding matrix by P12. Temporal and spatial matching of the disappearance of C3 by LCIC compartment (i.e., modules then matrix) with CD11b-positive MGC occupancy implicates complement signaling in the selective refinement of early LCIC connectivity. Multiple-labeling studies for a variety of established MGC markers (CD11b, CX3CR1, Iba1, TMEM119) indicate significant MGC heterogeneity in the LCIC as its compartments and segregated multisensory maps emerge. Marker colocalization was the exception rather than the rule, suggesting that unique MGC subpopulations exist in the LCIC and perhaps serve distinct developmental roles. Potential mechanisms whereby microglia sculpt early multisensory LCIC maps and how such activity/inactivity may underlie certain neurodevelopmental conditions, including autism spectrum disorder and schizophrenia, are discussed.
下丘外侧皮质（LCIC）是中脑的一个壳区，接收多模态输入，这些输入靶向其分区（模块化-基质）框架的离散区域。这种排列在小鼠出生后早期（出生后第0天至第12天，P0-P12）出现，此时体感和听觉输入分离为各自的模块化和基质终端模式。小胶质细胞（MGCs）在发育中的大脑中执行多种关键功能，其中包括识别活跃电路组装区域并选择性修剪过度生长或未充分利用的连接。其他脑结构的最新证据表明，在整个生命周期中，尤其是在既定的发育关键期，MGCs存在相当大的异质性。本研究探讨了经典补体级联信号（C3-CR3/CD11b）在完善早期多感觉网络中的潜在作用，并确定了在新生LCIC内表现出不同分子特征的几个小胶质细胞亚群。在整个定义的LCIC关键期及之后，对GAD67-绿色荧光蛋白（GFP）和CX3CR1-GFP小鼠进行免疫染色。GAD标记突出了新兴的LCIC模块化特征，而CX3CR1标记描绘了表达趋化因子受体的MGCs。C3表达在早期广泛分布于整个LCIC神经毡中，在P8时在模块化区域明显缺失，在关键期结束后更全面地消失。表达CD11b的小胶质细胞在出生时均匀分布，但在P8时偏向模块化区域，到P12时则偏向周围基质。LCIC分区（即模块然后是基质）中C3消失与CD11b阳性MGC占据的时间和空间匹配，暗示补体信号在早期LCIC连接性的选择性完善中起作用。对多种已确定的MGC标记物（CD11b、CX3CR1、Iba1、TMEM119）的多重标记研究表明，随着LCIC的分区和分离的多感觉图谱出现，LCIC中存在显著的MGC异质性。标记物共定位是例外而非规则，这表明LCIC中存在独特的MGC亚群，可能发挥不同的发育作用。本文讨论了小胶质细胞塑造早期多感觉LCIC图谱的潜在机制，以及这种活动/不活动如何可能成为某些神经发育疾病（包括自闭症谱系障碍和精神分裂症）的基础。
