Disruptions in reproductive health, sex hormonal profiles, and hypothalamic hormone receptors content in females of the C58/J mouse model of autism.

Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.

Altered hippocampal neurogenesis in a mouse model of autism revealed by genetic polymorphisms and by atypical development of newborn neurons.

Individuals with autism spectrum disorder (ASD) often exhibit atypical hippocampal anatomy and connectivity throughout their lifespan, potentially linked to alterations in the neurogenic process within the hippocampus. In this study, we performed an in-silico analysis to identify single-nucleotide polymorphisms (SNPs) in genes relevant to adult neurogenesis in the C58/J model of idiopathic autism. We found coding non-synonymous (Cn) SNPs in 33 genes involved in the adult neurogenic process, as well as in 142 genes associated with the signature genetic profile of neural stem cells (NSC) and neural progenitors. Based on the potential alterations in adult neurogenesis predicted by the in-silico analysis, we evaluated the number and distribution of newborn neurons in the dentate gyrus (DG) of young adult C58/J mice. We found a reduced number of newborn cells in the whole DG, a higher proportion of early neuroblasts in the subgranular layer (SGZ), and a lower proportion of neuroblasts with morphological maturation signs in the granule cell layer (GCL) of the DG compared to C57BL/6J mice. The observed changes may be associated with a delay in the maturation trajectory of newborn neurons in the C58/J strain, linked to the Cn SNPs in genes involved in adult hippocampal neurogenesis.

Relationship between the effect of polyunsaturated fatty acids (PUFAs) on brain plasticity and the improvement on cognition and behavior in individuals with autism spectrum disorder.

Objective: This work aimed to compile information about the neuronal processes in which polyunsaturated fatty acids (PUFAs) could modulate brain plasticity, in order to analyze the role of nutritional intervention with the ω-3 and ω-6 fatty acids as a therapeutic strategy for the Autism Spectrum Disorder (ASD)-related signs and symptoms.Methods: We reviewed different articles reporting the effect of PUFAS on neurite elongation, membrane expansion, cytoskeleton rearrangement and neurotransmission, considering the ASD-related abnormalities in these processes.Results: In accordance to the reviewed studies, it is clear that ASD is one of the neurological conditions associated with an impairment in neuronal plasticity; therefore, PUFAs-rich diet improvements on cognition and behavioral deficits in individuals with autism, could be involved with the regulation of neuronal processes implicated in the atypical brain plasticity related with this neurodevelopmental disorder.Discussion: The behavioral and cognitive improvement observed in individuals with ASD after PUFAs treatment might underlie, at least in part, in the ability of ω-3 and ω-6 fatty acids to induce neurite outgrowth, probably, through the dynamic regulation of the neuronal cytoskeleton along with the expansion of neuronal membranes. Furthermore, it might also be associated with an enhancement of the efficacy of synaptic transmission and the modulation of neurotransmitters release.

Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism.

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.

Dendritic complexity in prefrontal cortex and hippocampus of the autistic-like mice C58/J.

Autism spectrum disorder (ASD) has been associated to atypical neuronal connectivity in the prefrontal cortex (PFC) and the hippocampus, in part, due to an alteration in neuroplasticity processes such as dendritic remodeling. Moreover, it has been proposed that abnormal cytoskeletal dynamics might be underlying the disrupted formation and morphology of dendrites in the ASD brain. Hence, we performed an analysis of the complexity of dendritic arborization of the pyramidal neurons localized in the layer II/III of the PFC and the CA1 region of the hippocampus in the autistic-like mouse strain C58/J, which has previously demonstrated neuronal cytoskeleton anomalies. We found differences in length, number and branching pattern of dendrites of the pyramidal neurons from both structures of C58/J strain. These data suggest a lower dendritic arborization complexity that could be involved with the characteristic autistic-like behaviors displayed in C58/J mice.

Alterations in neuronal cytoskeletal and astrocytic proteins content in the brain of the autistic-like mouse strain C58/J.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficient social interaction, impaired communication as well as repetitive behaviors. ASD subjects present connectivity and neuroplasticity disturbances associated with morphological alterations in axons, dendrites, and dendritic spines. Given that the neuronal cytoskeleton and astrocytes have an essential role in regulating several mechanisms of neural plasticity, the aim of this work was to study alterations in the content of neuronal cytoskeletal components actin and tubulin and their associated proteins, as well as astrocytic proteins GFAP and TSP-1 in the brain of a C58/J mouse model of ASD. We determined the expression and regulatory phosphorylation state of cytoskeletal components in the prefrontal cortex, hippocampus, and cerebellum of C58/J mice by means of Western blotting. Our results show that autistic-like mice present: 1) region-dependent altered expression and phosphorylation patterns of Tau isoforms, associated with anomalous microtubule depolymerization; 2) reduced MAP2 A content in prefrontal cortex; 3) region-dependent changes in cofilin expression and phosphorylation, associated with abnormal actin filament depolymerizing dynamics; 4) diminished synaptopodin levels in the hippocampus; and 5) reduced content of the astrocyte-secreted protein TSP-1 in the prefrontal cortex and hippocampus. Our work demonstrates changes in the expression and phosphorylation of cytoskeletal proteins as well as in TSP-1 in the brain of the autistic-like mice C58/J, shedding light in one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain and laying the foundation for future investigations in this topic.