Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis

Brain and Behavior

Caty Casas²  Mireia Herrando-Grabulosa²  Raquel Manzano¹  Renzo Mancuso²  Rosario Osta¹ 

[1] Laboratory of Genetic Biochemistry (LAGENBIO-I3A), Aragón Institute of Health Sciences, Universidad de Zaragoza, Zaragoza, Spain;Group of Neuroplasticity and Regeneration, Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain

关键词: Amyotrophic lateral sclerosis;    ChAT;    MHC‐I;    motoneuron;    presynaptic boutons;    Tdp‐43;   

DOI  :  10.1002/brb3.104

来源: Wiley

【 摘 要 】

Abstract

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 SOD1^G93A 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 SOD1^G93A 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.

【 授权许可】

CC BY   
© 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

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