Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
Resumen: Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis.
Idioma: Inglés
DOI: 10.1002/brb3.104
Año: 2013
Publicado en: Brain and behavior 3, 2 (2013), 145-158
ISSN: 2162-3279

Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2009-12495
Tipo y forma: Artículo (Versión definitiva)
Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)

Creative Commons Debe reconocer adecuadamente la autoría, proporcionar un enlace a la licencia e indicar si se han realizado cambios. Puede hacerlo de cualquier manera razonable, pero no de una manera que sugiera que tiene el apoyo del licenciador o lo recibe por el uso que hace.


Exportado de SIDERAL (2020-10-23-13:53:36)


Este artículo se encuentra en las siguientes colecciones:
Artículos



 Registro creado el 2019-07-02, última modificación el 2020-10-23


Versión publicada:
 PDF
Valore este documento:

Rate this document:
1
2
3
 
(Sin ninguna reseña)