Investigating behavioral phenotypes related to autism spectrum disorder in a gene-environment interaction model of Cntnap2 deficiency and Poly I:C maternal immune activation

Haddad, Faraj L.; Oliveira, Cleusa De; Schmid, Susanne

doi:10.3389/fnins.2023.1160243

Cited by 7 publications

(4 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, they shed some light on the phenotypic heterogeneity associated with Cntnap2 heterozygous mutation, suggesting that mutations of this gene may constitute a causal factor for specific psychiatric pathology only and exclusively when associated with specific environmental factors, such as prenatal immune activation (12) or early-life stress. (B-F) Left panels: charts summarizing the quantification of the main effect of the covariates included in the model; Right charts: depict the results of multiple comparisons for the given outcome measure.…”

Section: Discussionmentioning

confidence: 99%

“…We reasoned that, the phenotypic heterogeneity related to CNTNAP2 haploinsufficiency may arise as a consequence of the gene-environment interaction, shaping specific phenotypic trajectories in response to early-life experiences occurring during critical stages of neurodevelopment. A previous study explored this possibility by exposing Cntnap2 +/to a prenatal Poly-I:C maternal immune activation, which exacerbates autistic-like behaviors in this model (12). In this work we sought to determine whether an environmental stressor during early-postnatal development may shape behavioral hallmarks associated with a specific CNTNAP2-related conditions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

Chelini,

Fortunato-Asquini,

Cerilli

et al. 2024

Preprint

View full text Add to dashboard Cite

The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities (ELA) are a major risk-factors for developing a psychiatric disorder. Yet, the mechanistic interaction between ELA and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. In this study we raised a mouse model with genetic predisposition to multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the Cntnap2+/- mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised Cntnap2+/+ littermates, as well as parallel groups of Cntnap2+/+ and Cntnap2+/- raised in standard conditions. Using a battery for behavioral phenotyping we show that ELA shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, we found that LBN-raised Cntnap2+/- mice develop a perseverative risk-taking behavior in the elevated plus maze and that this behavior is highly predictive of their success in the social interaction, assessed with the 3-chamber test. This finding suggests that the intrusion of anxiety into the social behavioral domain contributes to extreme gain- or loss-of function in social interaction, resembling a bipolar-like phenotype. Finally, we show that LBN promotes synaptic hypertrophy in the basolateral nucleus of the amygdala, but only in Cntnap2+/- raised in LBN this condition was found in combination with microglia abnormalities. We conclude that the interplay between ELA and Cntnap2 haploinsufficiency exacerbates bipolar-like behaviors in mice, and that this may be consequence of deficient synaptic homeostasis in the basolateral amygdala.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

Chelini,

Fortunato-Asquini,

Cerilli

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, Haddad et al. found that both MIA and Cntnap2 gene deficiency resulted in similar ASD-like behavioral deficits, but that both independently and synergistically exacerbated ASD-like symptoms in model rats when acted upon together ( 143 ). The opposite result was obtained by Kim et al.…”

Section: Interactions Of Genetics Environment Neural Pathways Neuroin...mentioning

confidence: 99%

Neuroplasticity of children in autism spectrum disorder

Chen,

Wang,

Zhang

et al. 2024

Front. Psychiatry

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that encompasses a range of symptoms including difficulties in verbal communication, social interaction, limited interests, and repetitive behaviors. Neuroplasticity refers to the structural and functional changes that occur in the nervous system to adapt and respond to changes in the external environment. In simpler terms, it is the brain’s ability to learn and adapt to new environments. However, individuals with ASD exhibit abnormal neuroplasticity, which impacts information processing, sensory processing, and social cognition, leading to the manifestation of corresponding symptoms. This paper aims to review the current research progress on ASD neuroplasticity, focusing on genetics, environment, neural pathways, neuroinflammation, and immunity. The findings will provide a theoretical foundation and insights for intervention and treatment in pediatric fields related to ASD.

show abstract

“…Partial or full deletion of the neurexin family ASD-risk gene Cntnap2 (contactin-associated protein-like 2) caused genotype-specific effects on adult female locomotor activity and sexindependent reduction in sociability in heterozygous and in PPI in hemizygous adolescent MIA (poly(I:C), GD9.5) offspring (Haddad et al, 2023), underscoring the importance of age, sex, and genetic dose on MIA-induced deficits. The full deletion alone caused increased startle response, hyperactivity, and moderate PPI reduction (exasperated by MIA) across ages.…”

Section: Introduction 30mentioning

confidence: 96%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

View full text Add to dashboard Cite

Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes. To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance. To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences. In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.

show abstract

Investigating behavioral phenotypes related to autism spectrum disorder in a gene-environment interaction model of Cntnap2 deficiency and Poly I:C maternal immune activation

Cited by 7 publications

References 81 publications

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

Neuroplasticity of children in autism spectrum disorder

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Contact Info

Product

Resources

About