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other·preclinical research, biomedical research, neurology, psychiatry·PMC10618093

Loss of spines in the prelimbic cortex is detrimental to working memory in mice with early-life adversity

Molecular Psychiatry · 9 authors, 4 centres

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TL;DR

This study used a mouse model to show that early-life adversity causes lasting loss of dendritic spines and postsynaptic connections in the prelimbic cortex, which correlates with impaired working memory. Activating the affected neurons with DREADDs improved the memory performance of the adversity-exposed mice.

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ELA was induced by altering the rearing environment during postnatal days 2-9. The study found ELA caused a lasting, selective loss of dendritic spines and postsynaptic density protein-95 (PSD-95) puncta on pyramidal cells in PrL layers II-III and V-VI. This spine loss correlated with impaired spatial working memory in a T-maze task. Electrophysiology in Thy1-expressing PrL cells revealed depressed glutamatergic transmission and decreased GluR1 and NR1 subunit expression in ELA mice. Chemogenetic activation of these PrL neurons via excitatory DREADDs improved working memory performance in ELA mice. The study demonstrates that ELA-induced structural deficits in PrL pyramidal cells are detrimental to glutamatergic transmission and frontal-dependent working memory.

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preclinical research

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ORIGINAL PAPER

PMC10618093

Loss of spines in the prelimbic cortex is detrimental to working memory in mice with early-life adversity

Molecular Psychiatry

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ABSTRACT

Adverse experiences in early life can shape neuronal structures and synaptic function in multiple brain regions, leading to deficits of distinct cognitive functions later in life. Focusing on the pyramidal cells of the prelimbic cortex (PrL), a main subregion of the medial prefrontal cortex, the impact of early-life adversity (ELA) was investigated in a well-established animal model generated by changing the rearing environment during postnatal days 2 to 9 (P2-P9), a sensitive developmental period. ELA has enduring detrimental impacts on the dendritic spines of PrL pyramidal cells, which is most apparent in a spatially circumscribed region. Specifically, ELA affects both thin and mushroom-type spines, and ELA-provoked loss of spines is observed on selective dendritic segments of PrL pyramidal cells in layers II-III and V-VI. Reduced postsynaptic puncta represented by postsynaptic density protein-95 (PSD-95), but not synaptophysin-labelled presynaptic puncta, in ELA mice supports the selective loss of spines in the PrL. Correlation analysis indicates that loss of spines and postsynaptic puncta in the PrL contributes to the poor spatial working memory of ELA mice, and thin spines may play a major role in working memory performance. To further understand whether loss of spines affects glutamatergic transmission, AMPA- and NMDA-receptor-mediated synaptic currents (EPSCs) were recorded in a group of Thy1-expressing PrL pyramidal cells. ELA mice exhibited a depressed glutamatergic transmission, which is accompanied with a decreased expression of GluR1 and NR1 subunits in the PrL. Finally, upregulating the activation of Thy1-expressing PrL pyramidal cells via excitatory DREADDs can efficiently improve the working memory performance of ELA mice in a T-maze-based task, indicating the potential of a chemogenetic approach in restoring ELA-provoked memory deficits.

CITATION EXPORT

Liping Xu, Yue Liu, Jingyi Long et al.. Loss of spines in the prelimbic cortex is detrimental to working memory in mice with early-life adversity. Molecular Psychiatry. (2023). https://doi.org/10.1038/s41380-023-02197-7

AUTHORS

9 · 4 CENTRES

Liping Xu, Yue Liu, Jingyi Long, Xiulan He, Fanbing Xie, Qiao Yin, Michael Chen, Dahong Long, Yuncai Chen

1https://ror.org/00zat6v61grid.410737.60000 0000 8653 1072Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436 China
2grid.10417.330000 0004 0444 9382Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands
3grid.19006.3e0000 0000 9632 6718University of California, Los Angeles, CA 90095 USA
4grid.266093.80000 0001 0668 7243Department of Pediatrics, University of California, Irvine, CA 92697 USA