Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress are Mitigated by Clozapine

Bristow, Greg C.; Dong, Erbao; Nwabuisi-Heath, Evelyn; Gentile, Sandro; Guidotti, Alessandro; Sodhi, Monsheel S.

doi:10.1101/2021.02.02.429408

Cited by 6 publications

(10 citation statements)

References 125 publications

(197 reference statements)

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“…In contrast, Clarke et al (2019) found increased social interaction in prenatally stressed C57BL/6J mice. More consistent data between laboratories has been reported in Swiss webster mice, where prenatal stress decreases social interaction in male offspring (G. Bristow et al, 2021; Matrisciano et al, 2013; Matrisciano et al, 2012). The effect of prenatal stress on social memory has not been tested previously to our knowledge.…”

Section: Discussionsupporting

confidence: 80%

“…The strains in each study varied such that prenatally stressed C57BL/6J mice exhibited behaviors associated with risk aversion while prenatally stressed Swiss Webster mice were more vulnerable to deficits in social behaviors. At a microscopic level, prenatal stress has been shown to affect glutamate receptors (Matrisciano et al, 2012; Orlando et al, 2014), GABAegic proteins(Matrisciano et al, 2018; Matrisciano et al, 2012), serotonin (Miyagawa et al, 2011), the HPA axis (Mueller & Bale, 2008; Salomon et al, 2011; Son et al, 2006), BDNF and DNMT (Dong et al, 2015; Matrisciano et al, 2012), RNA editing (Bristow et al, 2021), long-term potentiation (Son et al, 2006), and total glial cell count (Behan et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Prenatal Stress Modifies Spatial Cognition in Mice: Effects of Age and Sex

McCarthy,

Buck,

Sodhi

2024

Preprint

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Prenatal stress is linked with neuropathology of the cortical-hippocampal circuit, due to abnormal brain development that leads to long term neurological deficits in offspring, in both rodents and in humans with psychiatric disorders. Conflicting reports exist of the effects of prenatal stress in C57BL/6J mice, which is an inbred strain that is the most frequently used for neurobehavioral research. We now present comprehensive analyses of the effects of prenatal stress on spatial cognition and related behaviors in this inbred strain, in males and females at young adult and aged adult stages. The prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily from day 7 to day 18 of gestation. We tested the effects of prenatal stress on cognitive behavior using a battery of behavioral assays including the open-field test, the light-dark box, Morris water maze spatial acquisition and spatial reversal testing, in addition to assays of social interaction and social memory. We compared the behavioral phenotype of male and female offspring in young adult (10-20 weeks) and older adult ages (60- 70 weeks). Data reveal that male but not female mice had reduced body weight throughout the lifespan after exposure to prenatal stress. Young prenatally stressed adult females showed greater organization of tracking behavior in spatial acquisition tests than other groups. Prenatal stress improved reversal learning in aged females relative to non-stressed aged females. We detected decreased extinction of the spatial acquisition memory in prenatally stressed young adult mice of both sexes. Overall results indicate that prenatal stress may protect females from detrimental effects of age on function of the hippocampus. Our data support the finding that C57BL/6J are a relatively resilient strain of mouse that may be useful for investigating the differences between resilience and susceptibility to stress. Genomic differences between the C57BL/6J strain relative to Swiss Webster strain, which is more susceptible to prenatal stress are discussed. Future studies of prenatal stress in the C57BL/6J mouse strain should focus on the identification of molecular pathways that underlie resilience to prenatal stress, to identify novel targets for drug development.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Prenatal Stress Modifies Spatial Cognition in Mice: Effects of Age and Sex

McCarthy,

Buck,

Sodhi

2024

Preprint

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“…Fourth, we cannot fully rule out the possibility that both living and postmortem tissues may have differing medication effects. Still, it is worth emphasizing that even in tightly controlled experiments conducted by us and others, the overall influence of low and high doses of antipsychotics and small molecules on A-to-I editing profiles in the brain is insignificant 19,46 . Finally, we note that cell type-specific A-to-I sites were catalogued from postmortem tissues 13,32 , thus caution is warranted when interpreting their editing levels, especially for non-neuronal A-to-I sites, which are more vulnerable to postmortem-induced mechanisms.…”

Section: Discussionmentioning

confidence: 80%

Divergent landscapes of A-to-I editing in postmortem and living human brain

Rodriguez de los Santos,

Kopell,

Buxbaum Grice

et al. 2024

Preprint

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Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

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“…As in previous studies (Dong et al, 2015a;Bristow et al, 2021), litters for Swiss Webster mice in our laboratory contain 8-10 pups. Body weights of offspring from PRS and non-stressed (NS) groups at postnatal day 75 (late adolescence-early adulthood in mice) were not significantly different (p>0.1).…”

Section: Resultsmentioning

confidence: 99%

Prenatal Stress Alters Transcription of NMDA-Type Glutamate Receptors in the Hippocampus

Buck,

Dong,

Guidotti

et al. 2024

Preprint

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Prenatal stress damages the development of the cortico-hippocampal circuit in the brain and increases the risk for neurological disorders associated with deficits of social behavior, including schizophrenia. Accumulating evidence indicates that the NMDA-type glutamate receptor plays an important role in social cognition and stress-induced pathology in the hippocampus. In this study we have tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex and hippocampus of prenatally stressed mice. Prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily during gestational weeks 2 and 3. We treated the adult offspring with haloperidol (1mg/kg), clozapine (5mg/kg) or vehicle (saline) twice daily for 5 days, after which we measured social interaction behavior (SI) and locomotor activity. After euthanasia, we measured the transcription of NMDAR subunits in the hippocampus and frontal cortex. We observed that saline-treated prenatally stressed (PRS-Sal) mice had reduced social interaction (SI) behavior compared to controls (NS-Sal) (P<0.01). This deficit was recovered in PRS mice treated with clozapine (PRS-Clz) but not the haloperidol-treated PRS group (PRS-Hal). These changes were not due to suppressed locomotion as neither PRS nor antipsychotic treatment reduced locomotor activity. These effects of prenatal stress were associated with increased transcription of NMDAR subunits (GRIN genes) in the hippocampus but not the frontal cortex. We observed positive correlation between GRIN transcription and social behavior in the frontal cortex, and conversely, negative correlation between GRIN transcription and social behavior in the hippocampus. Studies indicate that transcription of NMDARs is activity dependent, therefore altering the transcription levels of different NMDAR subunits would have a significant impact on the excitatory transmission in the corticolimbic circuit. The results suggest a molecular pathway by which prenatal stress in mice leads to life-long deficits in social behavior. It's worth noting that while these associations have been observed in mice, the direct translation to human prenatal stress and NMDA receptor alterations requires further investigation. Nevertheless, these findings contribute to our understanding of the impact of prenatal stress on pathology in the hippocampus and downstream effects on social behavior and may have implications for understanding neuropsychiatric disorders related to prenatal stress exposure.

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Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress are Mitigated by Clozapine

Cited by 6 publications

References 125 publications

Prenatal Stress Modifies Spatial Cognition in Mice: Effects of Age and Sex

Prenatal Stress Modifies Spatial Cognition in Mice: Effects of Age and Sex

Divergent landscapes of A-to-I editing in postmortem and living human brain

Prenatal Stress Alters Transcription of NMDA-Type Glutamate Receptors in the Hippocampus

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