The role of distinct hippocampal calbindin neurons in modulating individual susceptibility to early life stress
Human Cognitive and Systems Neuroscience
Final Report Abstract
Stress-related disorders are a heavy burden and Millions of people worldwide are suffering from such disorders. In the current project, we have investigated the effects of a central regulator of stress system activity – the glucocorticoid receptor and its co-chaperone FKBP51, as they both have been implicated as genetic risk factors. However, the contribution of these risk factors, specifically of FKBP51, in district cellular populations in the brain remained elusive. To address this paucity, we tested in this project the importance of FKBP51 in mediating stress-related phenotypes in a cell-type specific manner. Initially we had proposed that the cell type that might be driving effects of early life adversity could be defined by the co-expression of calbindin, a ubiquitous Ca2+-binding protein that shows expression in subtypes of hippocampal glutamatergic and GABAergic neurons. However, initial analysis of co-expression of calbindin specifically with FKBP51, especially guided by available single cell RNA sequencing datasets, revealed only a modest overlap. We therefore focused the project on the analysis of FKBP51 contribution in glutamatergic vs GABAergic neurons on behavioral, structural and functional effects under baseline condition and following early life adversity. We could show using two different conditional knock out models that lack FKBP51 in either the glutamatergic or GABA-ergic neurons of the forebrain indeed affected behaviour, brain structure and gene expression in a sex-dependent and cell-divergent manner. Especially surprising was the findings that dependent on the affected cell type and sex of an animal, the resulting phenotype could be domainspecific, affecting either cognition or anxiety, and in opposite directions. Thus, labelling FKBP51 as a riskfactor turns out to be too blunt, and the same protein can actually promote either resilience or susceptibility dependent on the affected cell type and sex. Along the same lines, it was astonishing to find that early life adversity could in fact promote resilience through improvement of cognitive abilities under stressful conditions. Thus, mild to moderate adversity can actually prepare an individual to optimally deal with such situations later in live. This effect was again sex-specific and most prominent in female mice, underlining the importance of sex differences. Finally, our work could identify novel molecular targets that may play a central role in shaping individual stress vulnerability or resilience. While the initial hypothesis of a calbindin-positive neuronal population driving long-term effects of early-life stress in relation to FKBP51 could not be proven, a novel mechanism was uncovered with the identification of the transcription factor TCF4. Specifically, in females, activation of a TCF4-dependent gene expression network seems to have a pro-resilient effect, making this target interesting for further follow-up studies. Overall this project was highly successful, and resulted in a wealth of novel information and data, shedding light on the underlying mechanisms of stress-related psychiatric disorders and opening up new avenues for therapeutic intervention.
Publications
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Nectin-3 modulates the structural plasticity of dentate granule cells and long-term memory. Transl Psychiatry. 2017 Sep 5;7(9):e1228
Wang XX, Li JT, Xie XM, Gu Y, Si TM, Schmidt MV, Wang XD
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Suppressed Calbindin Levels in Hippocampal Excitatory Neurons Mediate Stress-Induced Memory Loss. Cell Rep. 2017 Oct 24;21(4):891-900
Li JT, Xie XM, Yu JY, Sun YX, Liao XM, Wang XX, Su YA, Liu YJ, Schmidt MV, Wang XD, Si TM
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Chronic Stress Reduces Nectin-1 mRNA Levels and Disrupts Dendritic Spine Plasticity in the Adult Mouse Perirhinal Cortex. Front Cell Neurosci. 2018 Mar 13;12:67
Gong Q, Su YA, Wu C, Si TM, Deussing JM, Schmidt MV, Wang XD
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Chronic social defeat stress in female mice leads to sex-specific behavioral and neuroendocrine effects. Stress. 2021 Mar;24(2):168-180
van Doeselaar L, Yang H, Bordes J, Brix L, Engelhardt C, Tang F, Schmidt MV
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Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinalhippocampal circuit contributes to early-life stress-induced memory deficits. Transl Psychiatry. 2022 Apr 4;12(1):141
Wu C, Gong Q, Xu X, Fang P, Wang C, Yu JY, Wang XX, Fang SH, Chen WJ, Lou HF, Liu YH, Wang L, Liu YJ, Chen W, Wang XD
