000079532 001__ 79532
000079532 005__ 20201023135900.0
000079532 0247_ $$2doi$$a10.1002/brb3.104
000079532 0248_ $$2sideral$$a111625
000079532 037__ $$aART-2013-111625
000079532 041__ $$aeng
000079532 100__ $$aCasas, C.
000079532 245__ $$aEarly presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
000079532 260__ $$c2013
000079532 5060_ $$aAccess copy available to the general public$$fUnrestricted
000079532 5203_ $$aSporadic 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.
000079532 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/SAF2009-12495
000079532 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000079532 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000079532 700__ $$aHerrando-Grabulosa, M.
000079532 700__ $$0(orcid)0000-0002-7477-8742$$aManzano, R.
000079532 700__ $$aMancuso, R.
000079532 700__ $$0(orcid)0000-0001-5687-6704$$aOsta, R.$$uUniversidad de Zaragoza
000079532 700__ $$aNavarro, X.
000079532 7102_ $$11001$$2420$$aUniversidad de Zaragoza$$bDpto. Anatom.,Embri.Genét.Ani.$$cÁrea Genética
000079532 773__ $$g3, 2 (2013), 145-158$$pBrain behav.$$tBrain and behavior$$x2162-3279
000079532 8564_ $$s11659727$$uhttps://zaguan.unizar.es/record/79532/files/texto_completo.pdf$$yVersión publicada
000079532 8564_ $$s115861$$uhttps://zaguan.unizar.es/record/79532/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000079532 909CO $$ooai:zaguan.unizar.es:79532$$particulos$$pdriver
000079532 951__ $$a2020-10-23-13:53:36
000079532 980__ $$aARTICLE