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2 Acta Neurobiologiae Experimentalis

2 2019

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Maternal immune activation during pregnancy alters the expression of mitochondrial dynamics markers in the brain of rat offspring

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Zawadzka A. , Cieslik M. , Gewartowska M. , Frontczak-Baniewicz M. , Adamczyk A.

2019

tom 79

nr Suppl.1

INTRODUCTION: Prenatal exposure to infection and subsequent inflammatory responses, as well as, mitochondrial dysfunction has been implicated in the pathogenesis of autism spectrum disorders (ASDs). However, the molecular links between infection-induced fetal brain changes, mitochondrial deregulation, and the autistic phenotype remain obscure. AIM(S): Analysis of maternal immune activation (MIA)-induced changes in the expression of mitochondrial dynamics markers in the brain of the neonatal and adolescent rat offspring. METHOD(S): The MIA model was induced by single intraperitoneal injection of lipopolysaccharide (100 μg/kg b.w.) to pregnant rats at embryonic day 9.5. On the 7th or 52-53rd post-natal day, rat offspring were decapitated, and the brains isolated. Transmission electron microscopy (TEM), quantitative real‑time PCR (qPCR), and immunoblotting were used to determine mitochondrial ultrastructure and mRNA/protein expression, respectively. RESULTS: The electron microscopic study demonstrated altered mitochondrial morphology, including fragmented cristae, expanded matrix compartment, and membrane disruption in both the cerebral cortex and hippocampus of adolescent MIA offspring. Moreover, changes were noted in the expression of proteins involved in the maintenance of mitochondrial morphology. We observed upregulated fusion machinery proteins – mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and Opa1 – as well as mitochondrial fission proteins – dynamin related protein‑1 (Drp1) and fission protein 1 (Fis1) – in the neonatal MIA brains. However, in adolescent animals exposed to prenatal infection, the expression of Mfn1, Mfn2 and Opa1 was significantly reduced; nevertheless, Drp1 and Fis1 remained increased CONCLUSIONS: MIA-evoked perturbations in the proteins regulating mitochondrial dynamics reveal potentially important aspects of the mechanism linking neuroinflammation, impaired mitochondrial function, and ASD. FINANCIAL SUPPORT: Supported by the POWER Och!Doc Program and NSC grant 2016/23/D/NZ4/03572.

Prenatal exposure to valproic acid leads to behavioral alterations and defects of synaptic proteins in the hippocampus of adolescent rats

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Adamczyk A. , Gassowska-Dobrowolska M. , Cieslik M. , Czapski G. A. , Jesko H. , Gewartowska M. , Frontczak-Baniewicz M.

2019

tom 79

nr Suppl.1

Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases characterized by impairment in communication and social interaction along with stereotyped or repetitive behaviors. Multiple studies have highlighted the involvement of synaptic proteins in the pathogenesis of ASDs. AIM(S): The aim of this study was to investigate the effect of fetal exposure to valproic acid (VPA) – a rodent model of environmentally triggered autism – on behavioral phenotype as well as gene expression of autism-associated synaptic proteins and synapse morphology in the hippocampus of adolescent rats. METHOD(S): Pregnant Wistar rats received a single intraperitoneal injection of VPA (450 mg/kg b.w.) on gestational day 12.5. Ultrasonic vocalization was analyzed in all infant rats at postnatal day (PND) 11 and anxiety‑related behavior in adolescent male offspring. At PND 52, male offspring were decapitated and the hippocampi were isolated. Transmission electron microscopy (TEM), qPCR, and immunoblotting were used to analyze synaptic structure and protein expression. RESULTS: VPA administration during pregnancy disturbed communication in neonatal rats and led to anxiety-like and repetitive behavior in adolescent animals. TEM showed synaptic pathology including nerve endings swelling, blurred and thickened synaptic cleft structure, and disruption of synaptic membranes. Ultrastructural changes were accompanied by increased expression of proteins involved in synaptic vesicle recycling and neurotransmitter release (Synaptobrevin, Synaptophysin, Synapsin‑1) and reduction in presynaptic membrane protein SNAP25 and the postsynaptic density scaffold PSD95. Changes also occurred in the expression of Shank family proteins and neuroligin 3. CONCLUSIONS: Deregulated expression of synaptic proteins could be involved in ASDs via alterations of synaptic structure/function, subsequently contributing to behavioral abnormalities. FINANCIAL SUPPORT: Supported by NSC grant 2017/25/B/NZ4/01969.