Early life stress impairs synaptic pruning in the developing hippocampus

Dayananda, Kiran K.; Ahmed, Sahabuddin; Wang, Daniel; Polis, Baruh; Islam, Rafiad; Kaffman, Arie

doi:10.1016/j.bbi.2022.09.014

Cited by 29 publications

(24 citation statements)

References 69 publications

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“…Consistent with previous findings (Dayananda et al, 2022), we determined that LB causes severe deficits in microglial mediated synaptic pruning during the second and third weeks of life, and clarified that these abnormalities are no longer present in P33 adolescent LB mice.…”

Section: Lb Impairs Microglial Mediated Synaptic Pruning At P17 But N...supporting

confidence: 90%

“…LB impairs microglial ramification and their ability to engulf synaptic material at P17, an age when the hippocampus undergoes intense synaptic pruning (Dayananda et al, 2022). To determine if these changes persisted in P33 adolescent mice and whether they differentially impacted males, we evaluated the effects of rearing, sex, and age in P17 and P33 mice.…”

Section: Resultsmentioning

confidence: 99%

“…Microglia play a crucial role in eliminating nonfunctional synapses during a critical period of development and disrupting this process leads to the retention of a large number of weak synapses, reduced connectivity, and abnormal behavior and cognition later in life (Bolton et al, 2022; Filipello et al, 2018; Johnson and Kaffman, 2017; Zhan et al, 2014). Moreover, significant impairments in microglial-mediated synaptic pruning occur in LB pups, as well as increased spine density that persists in adolescent mice (Bolton et al, 2022; Dayananda et al, 2022). In this study, we determined that LB causes severe synaptic and contextual fear conditioning deficits in adolescent male, but not female, littermates.…”

Section: Introductionmentioning

confidence: 99%

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Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Ahmed,

Polis,

Jamwal

et al. 2024

Preprint

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Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity.

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Section: Lb Impairs Microglial Mediated Synaptic Pruning At P17 But N...supporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Ahmed,

Polis,

Jamwal

et al. 2024

Preprint

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“…If the latter is the case, then we would expect other excitatory inputs to the dorsal striatum to show increased function. A recent study found that LBN disrupts synaptic pruning mechanisms in the hippocampus, resulting in increased dendritic arborization and c-Fos activation of CA1 pyramidal cells (Dayananda et al, 2023 ). Future investigations are warranted to determine how LBN impacts thalamic and hippocampal inputs to the dorsal striatum.…”

Section: Discussionmentioning

confidence: 99%

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

Carvalho

Khoja

Haile

et al. 2023

Front. Synaptic Neurosci.

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Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

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“…Many microglial functions are exquisitely responsive to local environmental cues(20,21,61,62), with synaptic pruning in particular garnering much attention. Compelling evidence suggests a causal role for microglial-mediated synaptic pruning in psychiatric disorders, such as schizophrenia (63,64) and studies using model systems have described sex-specific changes in microglial-mediated synaptic pruning following exposure to adverse environments (65,66). Together with these data, our results suggest further research into microglial mediated synaptic pruning, as a mechanism for sex-specific pathways in depression, is warranted.…”

Section: Discussionmentioning

confidence: 99%

Microglial function moderates the relation between depression risk factors and depression outcomes across the life course in females

Fitzgerald

Pokhvisneva

Patel

et al. 2023

Preprint

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Background Depression has an enormous socio-economic burden and is twice as common in women compared to men. Microglia are exceptionally responsive to environmental stimuli and their phenotype differs substantially by sex. We hypothesized microglial function would moderate the relation between depression risk factors and depressive outcomes in a sex-specific manner. Methods We used expression quantitative trait loci and single nucleus RNA-sequencing resources to generate polygenic scores (PGS) representative of individual variation in microglial function in the fetal (GUSTO; N=239-315, and ALSPAC; N=928-1461) and adult periods (UK Biobank; N=54753-72682). We stratified our analyses by sex and tested the interaction effects of these PGS with prenatal maternal depression symptoms and adult stressors, well-characterized depression risk factors. We used internalizing (early childhood) or depressive symptoms (late childhood and adulthood) as outcomes. Results The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and female offspring internalizing symptoms at 4 (GUSTO; beta=-0.25, 95%CI -0.44 to -0.06, P=0.008) and 7 years (GUSTO; beta=-0.16 , 95%CI -0.318 to -0.008, P=0.04), and depressive symptoms at 8.5-10 years (GUSTO; beta = -0.15, 95%CI = -0.25 to -0.03, P= 0.01) and 24 years (ALSPAC; beta=0.1, 95%CI 0.008 to 0.19, P=0.03). The adult microglial PGS moderated the relation between BMI (UK Biobank; beta=0.001, 95%CI 0.0009 to 0.003, P=7.74E-6) and financial insecurity (UK Biobank; beta=0.001, 95%CI 0.005 to 0.015, P=2E-4) with depressive symptoms in females. There were no significant interactions in males. Conclusion Our results illustrate an important role for microglial function in the conferral of sex-dependent depression risk.

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Early life stress impairs synaptic pruning in the developing hippocampus

Cited by 29 publications

References 69 publications

Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

Microglial function moderates the relation between depression risk factors and depression outcomes across the life course in females

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