scholarly journals Male-specific CREB signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability

2018 ◽  
Author(s):  
Marta Zamarbide ◽  
Adele Mossa ◽  
Molly K. Wilkinson ◽  
Heather L. Pond ◽  
Adam W. Oaks ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Neurodevelopmental Disorders ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Coiled Coil ◽  
Autism Spectrum ◽  
Behavioral Studies ◽  
Males And Females ◽  
Male Specific

ABSTRACTBackgroundThe prevalence of neurodevelopmental disorders is biased towards males with male: female ratios of 2:1 in intellectual disability (ID) and 4:1 in autism spectrum disorder (ASD). However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain containing 1A (CC2D1A), which is mutated in ID and ASD, we identified biochemical and behavioral differences between males and females, and explored whether CC2D1A controls male-specific intracellular signaling.MethodsCC2D1A is known to regulate phosphodiesterase 4D (PDE4D). We tested for activation PDE4D and downstream signaling molecules such as CREB in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in females to analyze learning and memory, social interactions, anxiety and hyperactivity. Finally, we targeted PDE4D activation with a PDE4D inhibitor to define how changes in PDE4D and CREB activity affect behavior in males and females.ResultsWe found that in Cc2d1a-deficient males PDE4D is hyperactive leading to a reduction in CREB signaling, but this molecular deficit is not present in females. Cc2d1a-deficient females only show impairment in novel object recognition, and no other cognitive and social deficits that have been found in males. Restoring PDE4D activity using an inhibitor rescues male-specific cognitive deficits, but has no effect on females.ConclusionsOur findings show that CC2D1A regulates intracellular signaling in a male-specific manner in the hippocampus leading to male-specific behavioral deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.

scholarly journals Developmental exposure to diesel exhaust upregulates transcription factor expression, decreases hippocampal neurogenesis, and alters cortical lamina organization: relevance to neurodevelopmental disorders

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Toby B. Cole ◽  
Yu-Chi Chang ◽  
Khoi Dao ◽  
Ray Daza ◽  
Robert Hevner ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Diesel Exhaust ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Hippocampal Neurogenesis ◽  
Behavioral Alterations ◽  
Developmental Exposure ◽  
Males And Females ◽  
Male Specific ◽  
Transcription Factor Expression

Abstract Background Exposure to traffic-related air pollution (TRAP) during development and/or in adulthood has been associated in many human studies with both neurodevelopmental and neurodegenerative diseases, such as autism spectrum disorder (ASD) and Alzheimer’s disease (AD) or Parkinson’s disease (PD). Methods In the present study, C57BL/6 J mice were exposed to environmentally relevant levels (250+/−50 μg/m3) of diesel exhaust (DE) or filtered air (FA) during development (E0 to PND21). The expression of several transcription factors relevant for CNS development was assessed on PND3. To address possible mechanistic underpinnings of previously observed behavioral effects of DE exposure, adult neurogenesis in the hippocampus and laminar organization of neurons in the somatosensory cortex were analyzed on PND60. Results were analyzed separately for male and female mice. Results Developmental DE exposure caused a male-specific upregulation of Pax6, Tbr1, Tbr2, Sp1, and Creb1 on PND3. In contrast, in both males and females, Tbr2+ intermediate progenitor cells in the PND60 hippocampal dentate gyrus were decreased, as an indication of reduced adult neurogenesis. In the somatosensory region of the cerebral cortex, laminar distribution of Trb1, calbindin, and parvalbumin (but not of Ctip2 or Cux1) was altered by developmental DE exposure. Conclusions These results provide additional evidence to previous findings indicating the ability of developmental DE exposure to cause biochemical/molecular and behavioral alterations that may be involved in neurodevelopmental disorders such as ASD.

scholarly journals Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders

2019 ◽  
Vol 27 (9) ◽  
pp. 1445-1455 ◽  
Author(s):  
Ron Nudel ◽  
Michael E. Benros ◽  
Morten Dybdahl Krebs ◽  
Rosa Lundbye Allesøe ◽  
Camilla Koldbæk Lemvigh ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protective Effect ◽  
Neurodevelopmental Disorders ◽  
Association Studies ◽  
Human Leukocyte ◽  
Population Based ◽  
Autism Spectrum ◽  
Small Samples ◽  
Hla Association ◽  
Hla Genes

AbstractHuman leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants’ HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

scholarly journals Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability

2019 ◽  
Vol 85 (9) ◽  
pp. 760-768 ◽  
Author(s):  
Marta Zamarbide ◽  
Adele Mossa ◽  
Pablo Muñoz-Llancao ◽  
Molly K. Wilkinson ◽  
Heather L. Pond ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Memory Deficits ◽  
Camp Signaling ◽  
Male Specific

scholarly journals Risk of neurodevelopmental disorders in children born from different ART treatments: a systematic review and meta-analysis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Tono Djuwantono ◽  
Jenifer Kiem Aviani ◽  
Wiryawan Permadi ◽  
Tri Hanggono Achmad ◽  
Danny Halim
Keyword(s):  
Systematic Review ◽  
Cerebral Palsy ◽  
Intellectual Disability ◽  
Assisted Reproductive Technology ◽  
Risk Ratio ◽  
Neurodevelopmental Disorders ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Reproductive Technology ◽  
Multiple Birth

Abstract Background Various techniques in assisted reproductive technology (ART) have been developed as solutions for specific infertility problems. It is important to gain consensual conclusions on the actual risks of neurodevelopmental disorders among children who are born from ART. This study aimed to quantify the relative risks of cerebral palsy, intellectual disability, autism spectrum disorder (ASD), and behavioral problems in children from different ART methods by using systematic review and meta-analysis. Healthcare providers could use the results of this study to suggest the suitable ART technique and plan optimum postnatal care. Methods Pubmed, Google Scholar, and Scopus databases were used to search for studies up to January 2020. Of the 181 screened full manuscripts, 17 studies (9.39%) fulfilled the selection criteria. Based on the Newcastle-Ottawa scale ratings, 7 studies were excluded, resulting in 10 studies that were eventually included in the meta-analyses. Mantel-Haenszel risk ratio model was used in the meta-analysis, and the results are described using forest plot with 95% confidence interval. Heterogeneity was assessed using the I2 value. Results Pooled evaluation of 10 studies showed that the risk of cerebral palsy in children from assisted reproductive technology (ART) is higher than children from natural conceptions (risk ratio [RR] 1.82, [1.41, 2.34]; P = 0.00001). Risk of intellectual disability (RR 1.46, [1.03, 2.08]; P = 0.03) and ASD (RR 1.49 [1.05, 2.11]; P = 0.03) are higher in intracytoplasmic sperm injection (ICSI) children compared to conventional in vitro fertilization (IVF) children. The differences in the risk of neurodevelopmental disorders in children born after frozen and fresh embryo transfers are not significant. Analysis on potential cofounder effects, including multiple birth, preterm birth, and low birth body weight highlight possibilities of significant correlation to the risks of neurodevelopmental disorders. Conclusions Pooled estimates suggest that children born after ART are at higher risk of acquiring cerebral palsy. ICSI treatment causes higher risk of intellectual disability and ASD. These findings suggest the importance of the availability of intensive care unit at the time of delivery and long-term developmental evaluation particularly in children from ICSI.

scholarly journals Association of maternal diabetes with neurodevelopmental disorders: autism spectrum disorders, attention-deficit/hyperactivity disorder and intellectual disability

2020 ◽  
Author(s):  
Shuyun Chen ◽  
Sixian Zhao ◽  
Christina Dalman ◽  
Håkan Karlsson ◽  
Renee Gardner
Keyword(s):  
Diabetes Mellitus ◽  
Attention Deficit Hyperactivity Disorder ◽  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Maternal Diabetes ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Spectrum Disorders

Abstract Background Maternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics). Methods This population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures. Results Overall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03–1.84), ID (2.09, 1.53–2.87) and ADHD (1.43, 1.16–1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID. Conclusion The association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

scholarly journals Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency

2020 ◽  
Vol 4 ◽  
pp. 239821282092864
Author(s):  
Brittany A Davis ◽  
François David ◽  
Ciara O’Regan ◽  
Manal A Adam ◽  
Adrian J Harwood ◽  
...  
Keyword(s):  
Information Processing ◽  
Mouse Model ◽  
Neurodevelopmental Disorders ◽  
Auditory Evoked Potentials ◽  
Autism Spectrum ◽  
Oscillatory Activity ◽  
Kleefstra Syndrome ◽  
Sensory Motor ◽  
Processing Deficits ◽  
Information Processing Deficits

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders. Haploinsufficiency of EHMT1, encoding a histone methyltransferase, is associated with several neurodevelopmental disorders, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency ( Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to neurodevelopmental disorders. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory, and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity. The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with EHMT1 haploinsufficiency.

scholarly journals Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders

2017 ◽  
Vol 23 (3) ◽  
pp. 544-555 ◽  
Author(s):  
N M Grissom ◽  
S E McKee ◽  
H Schoch ◽  
N Bowman ◽  
R Havekes ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodevelopmental Disorders ◽  
Reward Learning ◽  
Natural Reward ◽  
Male Specific

scholarly journals Direct glia-to-neuron transdifferentiation gives rise to a pair of male-specific neurons that ensure nimble male mating

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Laura Molina-García ◽  
Carla Lloret-Fernández ◽  
Steven J Cook ◽  
Byunghyuk Kim ◽  
Rachel C Bonnington ◽  
...  
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Male Mating ◽  
Sexually Dimorphic ◽  
Innate Behaviour ◽  
One Step ◽  
Males And Females ◽  
Direct Transdifferentiation ◽  
Male Specific ◽  
Mating Sequence

Sexually dimorphic behaviours require underlying differences in the nervous system between males and females. The extent to which nervous systems are sexually dimorphic and the cellular and molecular mechanisms that regulate these differences are only beginning to be understood. We reveal here a novel mechanism by which male-specific neurons are generated in Caenorhabditis elegans through the direct transdifferentiation of sex-shared glial cells. This glia-to-neuron cell fate switch occurs during male sexual maturation under the cell-autonomous control of the sex-determination pathway. We show that the neurons generated are cholinergic, peptidergic, and ciliated putative proprioceptors which integrate into male-specific circuits for copulation. These neurons ensure coordinated backward movement along the mate’s body during mating. One step of the mating sequence regulated by these neurons is an alternative readjustment movement performed when intromission becomes difficult to achieve. Our findings reveal programmed transdifferentiation as a developmental mechanism underlying flexibility in innate behaviour.

scholarly journals Rett syndrome: a sex-biased neurodevelopmental disorder

2017 ◽  
Vol 39 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Eyleen Goh
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Expression Profiles ◽  
Neurodevelopmental Disorder ◽  
Gene Expression Profiles ◽  
Autism Spectrum ◽  
Related Disorder ◽  
Genetic Sequences ◽  
Biochemical Profiles ◽  
Males And Females

Decades of research on neurodevelopmental disorders have focused on genetics. Although there has been significant progress, the aetiology of many neurodevelopmental disorders still remains unknown. Deciphering genetic sequences of the whole genome can identify disease-causing mutations in individuals. However, the same genetic sequences do not necessarily result in similar gene expression profiles, or the consequential biochemical profiles in every cell and in all individuals. In particular, studies have shown that differential biochemical profiles in males and females, possibly play a role in neurodevelopmental disorders being biased towards a different gender. Interestingly, autism spectrum disorder (ASD) is biased towards boys although it is not an X-linked disorder, whereas Rett syndrome, an ASD-related disorder where the disease-causing gene is located on the X-chromosome, is found almost exclusively in girls.

Novel Therapeutics in Childhood Onset Psychiatric Disorders

2013 ◽  
pp. 1061-1064
Author(s):  
Dorothy E. Grice ◽  
Alexander Kolevzon ◽  
Walter E. Kaufmann ◽  
Joseph D. Buxbaum
Keyword(s):  
Autism Spectrum Disorder ◽  
Clinical Trials ◽  
Down Syndrome ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Model Systems ◽  
Childhood Onset ◽  
Preclinical Evaluation ◽  
Novel Therapeutics

Neurodevelopmental disorders are frequently the result of genetic and genomic abnormalities associated with high risk for disease. Creating analogous mutations in cell and animal models permits the assessment of underlying neurobiological mechanisms, generates clues about useful therapeutic targets, and provides systems for preclinical evaluation of novel therapeutics. This chapter briefly summarizes several clinical trials in neurodevelopmental disorders, all based on neurobiological findings in model systems, including trials in Down syndrome (DS) and several monogenic forms of intellectual disability (ID) and/or autism spectrum disorder (ASD).

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