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. 2019 Apr 1;29(4):1634-1643.
doi: 10.1093/cercor/bhy061.

Microglial Pruning of Synapses in the Prefrontal Cortex During Adolescence

Allyson P Mallya  1 , Hui-Dong Wang  2 , Han Noo Ri Lee  1 , Ariel Y Deutch  1   2   3
Affiliations

Microglial Pruning of Synapses in the Prefrontal Cortex During Adolescence

Allyson P Mallya et al. Cereb Cortex. .

Abstract

Exaggerated synaptic elimination in the prefrontal cortex (PFC) during adolescence has been suggested to contribute to the neuropathological changes of schizophrenia. Recent data indicate that microglia (MG) sculpt synapses during early postnatal development. However, it is not known if MG contribute to the structural maturation of the PFC, which has a protracted postnatal development. We determined if MG are involved in developmentally specific synapse elimination in the PFC, focusing on adolescence. Layer 5 PFC pyramidal cells (PCs) were intracellularly filled with Lucifer Yellow for dendritic spine measurements in postnatal day (P) 24, P30, P35, P39, and P50 rats. In the contralateral PFC we evaluated if MG engulfed presynaptic (glutamatergic) and postsynaptic (dendritic spines) elements. Dendritic spine density increased from P24 to P35, when spine density peaked. There was a significant increase in MG engulfment of spines at P39 relative to earlier ages; this subsided by P50. MG also phagocytosed presynaptic glutamatergic terminals. These data indicate that MG transiently prune synapses of PFC PCs during adolescence, when the symptoms of schizophrenia typically first appear. An increase in MG-mediated synaptic remodeling of PFC PCs may contribute to the structural changes observed in schizophrenia.

Keywords: dendritic spine; microglia; pyramidal cell; schizophrenia; synaptic pruning.

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Figures

Figure 1.
Figure 1.
(A) Representative projection image of a basal dendritic segment from a L5 PFC PC intracellularly filled with Lucifer Yellow. Scale bar, 5 μm. (B) Orthogonal views showing the microglia and the dendritic spine in the same plane (white arrows) were used to verify colocalization. (C) and (D) Show examples of projection images of microglia with low (P24) and high (P39) levels, respectively, of colocalization (yellow puncta) of Iba1-labeled microglia (red) and PSD-95-ir dendritic spines (green). PSD-95-ir puncta were visible in the soma and in the processes (white arrows). Scale bars, 5 μm.
Figure 2.
Figure 2.
Spine density changes in L5 prefrontal cortical pyramidal cells as a function of age. Mean (±SEM) basal spine density differed significantly as a function of age. Spine density peaked at P35, and remained significantly higher than P24 at all ages thereafter. *P ≤ 0.01.
Figure 3.
Figure 3.
Dendritic spine morphology in prefrontal cortical L5 pyramidal cells across development. The frequency distributions of (A) spine length, (B) maximal spine head diameter, and (C) spine head volume were compared at P24, when microglial engulfment of spines was low, and P39, the age at which microglial engulfment of spines was high. The distribution of spine length at P39 was significantly different from that at P24, and was shifted to the left, indicating that spine length was shorter at P39. The frequency distributions of spine head diameter and volume were shifted to the right, signifying that shorter spines that have larger heads are more numerous at P39. *P ≤ 0.01; **P ≤ 0.0001.
Figure 4.
Figure 4.
Microglia soma size and density in the prefrontal cortex through adolescence. (A) The mean (± SEM) area of PFC microglial somata at P39 was significantly less than at P50. *P ≤ 0.05. (B) Microglial density was unchanged across development.
Figure 5.
Figure 5.
Microglial engulfment of dendritic spines during development in the prefrontal cortex. A sharp increase in microglial phagocytosis of dendritic spines was observed at P39 relative to earlier time points. By P50 microglial engulfment had subsided and was significantly lower than observed at P24. *P ≤ 0.05; **P ≤ 0.0001.
Figure 6.
Figure 6.
Microglia engulf excitatory presynaptic elements in the prefrontal cortex during adolescence. The engulfment of glutamatergic (VGluT1-ir) presynaptic elements by microglia was significantly increased at both P39 and P50 relative to P24. *P ≤ 0.05; **P ≤ 0.0001.
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