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Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior.

ABSTRACT: Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of ADK expression in the adult brain, but differences in the onset of ADK deletion. Specifically, we compared Nestin-Cre+/-:ADK-floxfl/fl (ADK?Brain) mice with global loss of ADK in the whole brain, beginning in mid-gestation and persisting for life, with Gfa2-Cre+/-:ADK-floxfl/fl (ADK?Astro) mice that have normal ADK expression throughout development, but lose astrocyte-specific ADK-expression in young adulthood. Because ADK-expression in adulthood is generally confined to astrocytes, adult ADK?Astro mice show a similar expression profile of ADK in key areas of the brain related to neuropsychiatric behavior, compared to adult ADK?Brain mice. We sought to determine a neurodevelopmental role of ADK on the expression of psychiatric behaviors in adult male and female mice. Adult ADK?Brain mice showed significant deficits in social memory in males, significant contextual learning impairments in both sexes, and a hyper-responsiveness to amphetamine in males. In contrast, ADK?Astro mice showed normal social memory and contextual learning but hypo-responsiveness to amphetamine in males. Our results demonstrate a key developmental role of ADK in mediating behaviors in adulthood related to neuropsychiatric disease and support the greater prevalence of these disorders among males.

SUBMITTER: Osborne DM

PROVIDER: S-EPMC6867705 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior.

Osborne D M DM Sandau U S US Jones A T AT Vander Velden J W JW Weingarten A M AM Etesami N N Huo Y Y Shen H Y HY Boison D D

Neuropharmacology 20180823

Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of A ...[more]

PMID: 30145320

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Project description:Importance:Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective:To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants:The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures:Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results:In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001). Conclusions and Relevance:The findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.

Project description:BACKGROUND:Expression patterns between males and females vary in every adult tissue, even in organs with no conspicuous dimorphisms such as the heart. While studies of male and female differences have traditionally focused on the influence of sex hormones, these do not account for all the differences at the molecular and epigenetic levels. We previously reported that a substantial number of genes were differentially expressed in male and female mouse embryonic stem (ES) cells and revealed dose-dependent enhancer activity in response to Prdm14, a key pluripotency factor expressed more highly in female ES cells. In this work, we investigated the role of Prdm14 in establishing sex-specific gene expression networks. We surveyed the sex-specific landscape in early embryogenesis with special reference to cardiac development. We generated sex-specific co-expression networks from mouse ES cells, examined the presence of sex-specific chromatin domains, and analyzed previously published datasets from different developmental time points to characterize how sex-biased gene expression waxes and wanes to evaluate whether sex-biased networks are detectable throughout heart development. RESULTS:We performed ChIP-seq on male and female mouse ES cells to determine differences in chromatin status. Our study reveals sex-biased histone modifications, underscoring the potential for the sex chromosome complement to prime the genome differently in early development with consequences for later expression biases. Upon differentiation of ES cells to cardiac precursors, we found sex-biased expression of key transcription and epigenetic factors, some of which persisted from the undifferentiated state. Using network analyses, we also found that Prdm14 plays a prominent role in regulating a subset of dimorphic expression patterns. To determine whether sex-biased expression is present throughout cardiogenesis, we re-analyzed data from two published studies that sampled the transcriptomes of mouse hearts from 8.5 days post-coitum embryos to neonates and adults. We found sex-biased expression at every stage in heart development, and interestingly, identified a subset of genes that exhibit the same bias across multiple cardiogenic stages. CONCLUSIONS:Overall, our results support the existence of sexually dimorphic gene expression profiles and regulatory networks at every stage of cardiac development, some of which may be established in early embryogenesis and epigenetically perpetuated.

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Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior.

Publications

Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior.

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