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Delayed Outgrowth in Response to the BDNF and Altered Synaptic Proteins in Neurons From SHR Rats

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Abstract

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity symptoms. Neuroimaging studies have revealed a delayed cortical and subcortical development pattern in children diagnosed with ADHD. This study followed up on the development in vitro of frontal cortical neurons from Spontaneously hypertensive rats (SHR), an ADHD rat model, and Wistar-Kyoto rats (WKY), control strain, over their time in culture, and in response to BDNF treatment at two different days in vitro (DIV). These neurons were also evaluated for synaptic proteins, brain-derived neurotrophic factor (BDNF), and related protein levels. Frontal cortical neurons from the ADHD rat model exhibited shorter dendrites and less dendritic branching over their time in culture. While pro- and mature BDNF levels were not altered, the cAMP-response element-binding (CREB) decreased at 1 DIV and SNAP-25 decreased at 5 DIV. Different from control cultures, exogenous BDNF promoted less dendritic branching in neurons from the ADHD model. Our data revealed that neurons from the ADHD model showed decreased levels of an important transcription factor at the beginning of their development, and their delayed outgrowth and maturation had consequences in the levels of SNAP-25 and may be associated with less response to BDNF. These findings provide an alternative tool for studies on synaptic dysfunctions in ADHD. They may also offer a valuable tool for investigating drug effects and new treatment opportunities.

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Data Availability

Data will be made available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from Brazilian agencies (CNPq, CAPES) and FAPERGS. The CAPES fellowship supported DMM and MVSL. ASA and CBAO were a recipient of the CNPq fellowship. ACLM was supported by the PIBIC—UFRGS (CNPq) fellowship.

Funding

This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-FCT), Programa de Apoio aos Núcleos de Excelência (PRONEX/FAPERGS), Fundação de Apoio à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

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  1. Departamento de Bioquímica, Programa de Pós-Graduação Em Ciências Biológicas—Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600—anexo, Porto Alegre, RS, 90035-003, Brasil

    Daniela M. Marques, Amanda S. Almeida, Catiane B. A. Oliveira, Ana Carolina L. Machado, Marcus Vinícius S. Lara & Lisiane O. Porciúncula

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Contributions

DMM and LOP conceived and designed the study. DMM, ASA, CBAO, MVSL and ACLM performed all experiments. DMM and LOP performed statistical analysis. LOP and DMM interpreted data, wrote, prepared figures, and revised the manuscript. LOP coordinated the study. All authors revised and contributed to the final version of this manuscript.

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Correspondence to Lisiane O. Porciúncula.

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All experimental protocols were approved by the ethical committee of the Federal University of Rio Grande do Sul and all procedures in this study followed the rules of the NIH Guide for Care and Use of Laboratory Animals as well as the Brazilian Society for Neuroscience and Behavior (SBNeC) recommendations for animal care.

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Marques, D.M., Almeida, A.S., Oliveira, C.B.A. et al. Delayed Outgrowth in Response to the BDNF and Altered Synaptic Proteins in Neurons From SHR Rats. Neurochem Res 48, 2424–2435 (2023). https://doi.org/10.1007/s11064-023-03917-9

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