A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

Léger, Marianne; Neill, Joanna C.

doi:10.1016/j.neubiorev.2016.06.029

Cited by 66 publications

(52 citation statements)

References 165 publications

(176 reference statements)

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“…Finally, it must be noted that all our experiments were performed in male mice. However, there are well-known sex-differences in the onset and progression of schizophrenia (with first-time hospitalizations occurring at a younger age in men than in women), as well as sex-specific differences in the performance of most of the cognitive tasks that we tested here in both animals and humans (for review see Hill, 2016; Leger and Neill, 2016). Therefore, future studies must also compare the effectiveness of NAC as a potential treatment in female populations.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70–120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

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Section: Discussionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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“…Since 2014, they implement policies that oblige applicants to report their plans for the balance of male and female cells and animals in preclinical studies (Clayton & Collins, ). Most nervous system diseases, including multiple sclerosis, Parkinson's disease, schizophrenia, autism, depression, and dementia affect women and men differentially with respect to prevalence, severity, or disease course (Christensen et al, ; Golden & Voskuhl, ; Haaxma et al, ; Kokras & Dalla, ; Leger & Neill, ; Tschanz et al, ). So, it would seem adequate for preclinical research using mouse models of these diseases to include subjects of both sexes in all experiments.…”

Section: Introductionmentioning

confidence: 99%

“…So, it would seem adequate for preclinical research using mouse models of these diseases to include subjects of both sexes in all experiments. However, this is still not common practice (Kokras & Dalla, ; Leger & Neill, ; Zucker & Beery, ). Even in 2015, of the 71 research articles that used rodents published in the journal Pain, only 3 affirmed the use of both sexes (Mogil, ).…”

Section: Introductionmentioning

confidence: 99%

Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

Fritz

Amrein

Wolfer

2017

American J of Med Genetics Pt C

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Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water‐maze and in 4,554 mice tested in the same open field arena. Confidence intervals for Cohen's d as measure of effect size were computed and tested for equivalence with 0.2 as equivalence margin. Despite the large sample size, only few behavioral parameters showed a significant sex effect on CV. Confidence intervals of effect size indicated that CV was either equivalent or showed a small sex difference at most, accounting for less than 2% of total group to group variation of CV. While female mice were potentially slightly more variable in water‐maze acquisition and in the open field, males tended to perform less reliably in the water‐maze probe trial. In addition to evaluating variability, we also directly compared mean performance of female and male mice and found them to be equivalent in both water‐maze place navigation and open field exploration. Our data confirm and extend other large scale studies in demonstrating that including female mice in experiments does not cause a relevant increase of data variability. Our results make a strong case for including mice of both sexes whenever open field or water‐maze are used in preclinical research.

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“…This suggests a shared SCZ/BD spectrum, but leaves the causes for the widely divergent sex-specific manifestations of these clinical pathologies largely unclear. Compared with women, men present a higher prevalence of SCZ (odds ratio [OR] = 1.4), a 10 years earlier mean age of highest disease risk (15-25 versus 25-35 years of age) and a worse prognosis (Leger and Neill, 2016). In comparison, BD incidence is not dissimilar in men and women, but 80%-90% of ''rapid cyclers'' with a particularly bad prognosis are women, and major depressive disorder (MDD), which is a prerequisite for BD diagnosis, affects women more often (OR = 2) (Berger, 2014).…”

Section: Introductionmentioning

confidence: 99%

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

et al. 2019

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Graphical Abstract Highlights d Single-cell transcriptomes reveal a unique profile of cortical cholinergic neurons d Female-and male-derived cells show distinct neurokineinduced miRNA responses d Differentially enriched microRNA families constitute a selforganizing network d Integrative analysis identifies mir-10/mir-199 regulators of cholinergic function SUMMARYRNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male-and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

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A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

Cited by 66 publications

References 165 publications

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

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