4.7 Article

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

期刊

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.839715

关键词

autism spectrum disorder; dopaminergic system; caspase 8; electron microscopy; synapsis; behavioral test

资金

  1. Spanish Ministerio de Economia y Competitividad [RTI2018-098645-B-I00]
  2. Junta de Andalucia (Consejeria de Economia y Conocimiento) [P18-RT-1372, US-1264806]
  3. MINECO [PID2019-109569GB-I00]
  4. Fondo Europeo de Desarrollo Regional (FEDER)-UE A way to build Europe from the Ministerio de Economia y Competitividad [RTI2018-099778-B-I00]
  5. Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social [2019I041]
  6. Ministerio de Salud-Instituto de Salud Carlos III [PI18/01691]
  7. Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud y Familias, Junta de Andalucia [PI-0080-2017, PI-0009-2017]
  8. Consejeria de Salud y Familias, Junta de Andalucia [PI-0134-2018, PEMP-0008-2020]
  9. Consejeria de Transformacion Economica, Industria, Conocimiento y Universidad, Junta de Andalucia [P20_00958, CTS-510]
  10. CEIMAR [CEIJ-003]
  11. Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz-INiBICA [LI19/06IN-CO22, IN-C09]
  12. CIBERSAM [CB07/09/0033]
  13. European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [955684]
  14. Marie Curie Actions (MSCA) [955684] Funding Source: Marie Curie Actions (MSCA)

向作者/读者索取更多资源

New non-apoptotic roles have been discovered for apoptotic caspases, which are important in shaping the brain during early development by eliminating excessive and nonfunctional synapses and cells. Impairments in this process can contribute to neurological and mental illnesses. Additionally, low dopamine functioning appears to be associated with autism spectrum disorders.
In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.

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