ABSTRACT
Autism spectrum disorder (ASD) is a heterogeneously childhood neurodevelopmental disorder, believed to be under development of various genetic and environmental factors. Autophagy and related pathways have also been implicated in the etiology of ASD. We aimed to investigate autophagic markers by generating the transgenerational inheritance of ASD-like behaviors in the Cc2d1a animal model of ASD. Cc2d1a (+/-) mouse model of ASD was built in two different groups by following three generations. After behavior test, bilateral hippocampus was sliced. Western Blot assay and quantitative real-time polymerase chain reaction (QRT-PCR) were used for measurement of LC3 and Beclin-1 as key regulators of autophagy. All of the animal and laboratory studies were conducted in the Erciyes University Genome and Stem Cell Center (GENKOK). Significant LC3 and Beclin-1 mRNA expression levels were observed in mouse hippocampus between groups and generations. Western blot confirmed the changes of the proteins in the hippocampus. LC3 expressions were increased for females and decreased for males compared to the control group. Beclin-1 expression levels were found to be significantly decreased in males and females compared to controls. This study could help explain a new pathway of autophagy in ASD mouse models. Future animal studies need to investigate sex differences in mouse modeling autism-relevant genes like CC2D1A. We anticipate our results to be a starting point for more comprehensive autophagy studies in this mouse model of ASD.
Subject(s)
Autism Spectrum Disorder/pathology , Autophagy/physiology , Repressor Proteins/deficiency , Aggression , Animals , Anxiety/etiology , Anxiety/genetics , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/psychology , Beclin-1/biosynthesis , Beclin-1/genetics , Beclin-1/physiology , Crosses, Genetic , Disease Models, Animal , Exploratory Behavior , Female , Gene Expression Regulation , Genes, Lethal , Heterozygote , Hippocampus/metabolism , Male , Mice , Mice, Inbred BALB C , Microtubule-Associated Proteins/biosynthesis , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/physiology , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Repressor Proteins/genetics , Repressor Proteins/physiology , Sex CharacteristicsABSTRACT
Autism spectrum disorder (ASD) is characterized by repetitive stereotypic behaviors, restricted interests, social withdrawal, and communication deficits. Aggression and insensitivity to pain are largely unexplained in these cases. We analyzed nine mRNA expressions of the candidate genes related to aggression and insensitivity to pain in the peripheral blood of patients with ASD. Whole blood samples were obtained from 40 autistic patients (33 boys, 7 girls) and 50 age- and sex-matched controls (37 boys and 13 girls) to isolate RNA. Gene expression was assessed by quantitative Real-Time PCR (qRT-PCR) in the Erciyes University Genome and Stem Cell Center (GENKOK). All of the gene expressions except CRHR1 and SLC6A4 were found to be statistically different between the ASD patients and controls. Gene expression also differed according to gender. Alterations in the mRNA expression patterns of the HTR1E, OPRL1, OPRM1, TACR1, PRKG1, SCN9A and DRD4 genes provide further evidence for a relevant effect of the respective candidate genes on the pathophysiology of ASD. Future studies may determine the sensitivity of these candidate markers in larger samples including further neuropsychiatric diagnosis.
Subject(s)
Autism Spectrum Disorder/genetics , NAV1.7 Voltage-Gated Sodium Channel/genetics , RNA, Messenger/blood , Receptor, Serotonin, 5-HT1A/genetics , Receptors, Dopamine D4/genetics , Receptors, Opioid/genetics , Aggression , Autism Spectrum Disorder/blood , Autism Spectrum Disorder/physiopathology , Biomarkers/blood , Child, Preschool , Cyclic GMP-Dependent Protein Kinase Type I/genetics , Cyclic GMP-Dependent Protein Kinase Type I/metabolism , Female , Humans , Male , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pain Perception , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D4/metabolism , Receptors, Opioid/metabolismABSTRACT
Intracranial hemorrhage due to vitamin K deficiency is a serious disease that can lead to morbidity, mortality, and mental retardation. Our goal in this study is to determine the frequency of VKORC1-1639 G>A polymorphism in patients who have undergone intracranial hemorrhage due to vitamin K deficiency bleeding (VKDB). To study VKORC1-1639 G>A polymorphism, blood was drawn from patients (n = 51, age 8:0 ± 6:5 years) followed at the Pediatric Neurology and Hematology section, Faculty of Medicine, Erciyes University, between 1990 and 2016, diagnosed with VKDB as idiopathic or from patients diagnosed with intracranial hemorrhage due to secondary vitamin K deficiency and also from volunteers (n = 51, age 11 ± 4.5 years). Intensive care and nutrition needs of patients and the laboratory radiological imaging results and treatments that were applied were analyzed through scanning the files of the patients and information received from families. Through detailed physical examination, patients with neurologic sequelae and ongoing epilepsy were determined. The results were compared to clinical and laboratory results with control group. Eight (15.7%) of the patients were normal, 29 (56.9%) heterozygous carrier, and 14 (27.5%) homozygous mutants. In the control group, 19 (37.3%) were normal, 19 (37.3%) heterozygous carriers, and 13 (25.5%) homozygous mutants. The VKOR1-1639>A (SNP:rs9923231) mutant positivity (homozygous plus heterozygous mutant) was significantly higher in the patient group when compared to controls. There were no significant differences between patient and control groups in terms of the prognosis.
