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

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.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice

“…Based upon normal locomotion in the OFT, the errors in finding the escape hole in the spatial cued-recall task were not likely due to alterations in processing the visual cues [65] or motor ability, but were likely due to deficits in brain circuitry as suggested by a positive correlation between poor spatial memory and decreased spine density on PrL neurons in Rfwd2 +/− male mice. The synaptic connections between PrL layer II/III pyramidal neurons and other brain areas [66,67] are important for social behavior, communication, cognition and anxiety [30,45]. Dysregulation of these PrL projections causes autistic-like and anxiety-like behaviors [29].…”

“…Animals were randomly assigned to the experimental groups. The sample size (n) for different experiments is indicated in each figure legend and was determined according to the preliminary results and the standards generally used in the field [29,35,45]. Results were analyzed by two population Student's t-test, or two-way ANOVA followed by post hoc Bonferroni's test, or two-way repeated measures (RM) ANOVA followed by post hoc Sidak's test, as indicated in the figure legends.…”