Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life

Fehr, Tristan; Janssen, William G.M.; Park, Janis; Baxter, Mark G.

doi:10.1016/j.isci.2022.105685

Cited by 11 publications

(6 citation statements)

References 103 publications

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“…The image stacks were imported into Volume Annotation and Segmentation Tool (VAST Lite) (Berger et al,2018) for three-dimensional reconstruction of presynaptic boutons and their mitochondria, and the associated synapse surface area. We employed similar sampling methods to prior work in macaque monkeys (Hara et al,2011, 2014, 2016; Fehr et al, 2022). The experimenter performing the segmentations was blind to the subject-identifying information of the images.…”

Section: Methodsmentioning

confidence: 99%

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Glavis-Bloom

Vanderlip

Novak

et al. 2022

Preprint

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Working memory relies critically on the dorsolateral prefrontal cortex (dlPFC). Morphology and function of the dlPFC, and corresponding working memory performance, are affected early in the aging process. However, these effects are heterogeneous, with nearly half of aged individuals spared of working memory deficits. Translationally relevant model systems are critical for investigating the neurobiological drivers of this variability and identifying why some people experience age-related working memory impairment while others do not. The common marmoset (Callithrix jacchus) is advantageous as a model in which to investigate the biological underpinnings of aging because, as a nonhuman primate, marmosets have a clearly defined dlPFC facilitating investigations of prefrontal-dependent cognitive functions, including working memory, and their short (~10 year) lifespan facilitates longitudinal studies of aging. Here, we conduct the first investigation of synaptic ultrastructure in the dlPFC of the marmoset and investigate whether there are changes to synaptic ultrastructure that are unique to aging with and without working memory impairment. To do this, we characterized working memory capacity in a cohort of marmosets that collectively covered their short lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Utilizing three dimensional reconstruction from serial section electron microscopy, we visualized structural correlates of synaptic efficacy including boutons, mitochondria, and synapses in layer III of the dlPFC of three marmosets: one young adult (YA), one aged cognitively unimpaired (AU), and one aged cognitively impaired (AI). We find that aged marmosets have fewer synapses in dlPFC than young, and this is due to selective vulnerability of small synapses. Next, we tested the hypothesis that violation of the ultrastructural size principle underlies age-related working memory impairment. The ultrastructural size principle states that synaptic efficacy relies on coordinated scaling of synaptic components (e.g., synapses, mitochondria) with presynaptic boutons. While synapses and mitochondria scaled proportionally and were strongly correlated with presynaptic boutons in the YA and AU marmosets, the ultrastructural characteristics of the AI marmoset were alarmingly different. We found that age-related working memory impairment was associated with disproportionately large synapses compared to presynaptic boutons, specifically in those with mitochondria. Remarkably, presynaptic mitochondria and these boutons were completely decorrelated. We posit that this decorrelation results in mismatched energy supply and demand, leading to impaired synaptic transmission. This is the first report of age-related synapse loss in the marmoset, and the first demonstration that violation of the ultrastructural size principle underlies age-related working memory impairment.

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Section: Methodsmentioning

confidence: 99%

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Glavis-Bloom

Vanderlip

Novak

et al. 2022

Preprint

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“…In contrast, rat cortical tissue exhibited a significant shift toward a fragmented mitochondrial phenotype, when analyzed months following P7 SEV exposure ( 67 ). In a recently published article involving NHP, subtle, but statistically significant changes in mitochondrial morphology were observed only in the hippocampal region 4 years after early postnatal SEV treatment ( 7 ). The authors suggested these findings were indicative of disruption in the fission-fusion axis, although no molecular results substantiated this assertion ( 7 ).…”

Section: Mitochondrial Targets Of Ga Damagementioning

confidence: 99%

“…In a recently published article involving NHP, subtle, but statistically significant changes in mitochondrial morphology were observed only in the hippocampal region 4 years after early postnatal SEV treatment ( 7 ). The authors suggested these findings were indicative of disruption in the fission-fusion axis, although no molecular results substantiated this assertion ( 7 ). Taken together, these results indicate that in vivo GA exposure can induce a shift in mitochondrial morphology, which may differ both regionally and temporally.…”

Section: Mitochondrial Targets Of Ga Damagementioning

confidence: 99%

“…In neurons, mitochondria are localized to the synapse to supply both ATP and calcium ions required for neurotransmission ( 38 ). Multiple in vivo reports have observed reduced mitochondrial density (number of mitochondria per area) in the neural synapse, in both rat [with SEV ( 56 , 72 ) and ISO ( 55 )] and NHP models [with SEV ( 7 )], after GA exposure. It is interesting to note that Amrock et al observed that this effect increased with a higher SEV exposure time, though there was no difference when the total exposure was divided into multiple smaller time intervals (single 6 h exposure vs. two 3 h exposures) ( 72 ).…”

Section: Mitochondrial Targets Of Ga Damagementioning

confidence: 99%

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The effects of general anesthetics on mitochondrial structure and function in the developing brain

2023

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The use of general anesthetics in modern clinical practice is commonly regarded as safe for healthy individuals, but exposures at the extreme ends of the age spectrum have been linked to chronic cognitive impairments and persistent functional and structural alterations to the nervous system. The accumulation of evidence at both the epidemiological and experimental level prompted the addition of a warning label to inhaled anesthetics by the Food and Drug Administration cautioning their use in children under 3 years of age. Though the mechanism by which anesthetics may induce these detrimental changes remains to be fully elucidated, increasing evidence implicates mitochondria as a potential primary target of anesthetic damage, meditating many of the associated neurotoxic effects. Along with their commonly cited role in energy production via oxidative phosphorylation, mitochondria also play a central role in other critical cellular processes including calcium buffering, cell death pathways, and metabolite synthesis. In addition to meeting their immense energy demands, neurons are particularly dependent on the proper function and spatial organization of mitochondria to mediate specialized functions including neurotransmitter trafficking and release. Mitochondrial dependence is further highlighted in the developing brain, requiring spatiotemporally complex and metabolically expensive processes such as neurogenesis, synaptogenesis, and synaptic pruning, making the consequence of functional alterations potentially impactful. To this end, we explore and summarize the current mechanistic understanding of the effects of anesthetic exposure on mitochondria in the developing nervous system. We will specifically focus on the impact of anesthetic agents on mitochondrial dynamics, apoptosis, bioenergetics, stress pathways, and redox homeostasis. In addition, we will highlight critical knowledge gaps, pertinent challenges, and potential therapeutic targets warranting future exploration to guide mechanistic and outcomes research.

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“…[9][10][11][12] Electron microscopic analyses of NHP brain tissue after neonatal exposure to sevoflurane suggest that early-in-life exposure causes alterations in the synaptic ultrastructure later in life. 13 Four years after multiple 4-hour exposures to sevoflurane during infancy, the brains of exposed animals showed a significant reduction in synapse areas in the CA1 area of the hippocampus, while the synapse density was unaffected. Of note, the same animals had shown functional alterations such as heightened emotional reactivity to social stressors and impairments in visual recognition memory starting at the age of 6 months and 1 year, respectively.…”

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confidence: 99%

An Update on Preclinical Research in Anesthetic-Induced Developmental Neurotoxicity in Nonhuman Primate and Rodent Models

Neudecker

Thomas

et al. 2022

Journal of Neurosurgical Anesthesiology

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T he 2022 Pediatric Anesthesia and NeuroDevelopment Assessment (PANDA) Meeting included an update on preclinical research in the field of anestheticinduced developmental neurotoxicity (AIDN), with a focus on key developments since last meeting 3 years prior. The focus was on two areas: (1) The rapid growth in reports from nonhuman primate (NHP) studies, which play a pivotal role in understanding what elements of AIDN are likely to translate to human patients; and (2) The exploration of new targets, phenotypes, and exposure paradigms that have been conducted in rodent models. The purpose of this commentary article is to summarize this discussion and expand upon it both to update the reader on key developments in AIDN research and to highlight the importance of continued animal model research. UPDATE ON NONHUMAN PRIMATE STUDIES OF AIDNThe nonhuman primate (NHP) model is of value to the field of AIDN as clinical approaches are limited due to the ethical considerations of pediatric studies. The NHP is phylogenetically close to the human condition, sharing similarities in the development and complexity of their brain, in their cognitive functions, and in behavioral repertoire. Both species show similarities in social cohabitation, and social signals in both species depend on visual cues. In contrast, small animals such as rodents strongly rely on olfactory signals. Studies exposing infant NHPs to anesthetics have greatly contributed to the field of AIDN. 1 The most recent advances, including new knowledge about structural alterations and functional outcomes induced by early-in-life anesthesia exposure and the latest findings in neuroimaging studies and investigations of underlying mechanisms and mitigating strategies, are discussed. Newly Identified Structural AlterationsEarly histopathological studies in NHPs specified the complex gyrencephalic brain and expanded the understanding of acute neurotoxic effects on the immature brain caused by the exposure to diverse anesthetics that had been described from studies in rodent pups. [2][3][4][5][6][7] As little as 3 hours exposure to isoflurane on postnatal day 6

show abstract

Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life

Cited by 11 publications

References 103 publications

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

The effects of general anesthetics on mitochondrial structure and function in the developing brain

An Update on Preclinical Research in Anesthetic-Induced Developmental Neurotoxicity in Nonhuman Primate and Rodent Models

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