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

Casas, Caty; Herrando-Grabulosa, Mireia; Manzano, Raquel; Mancuso, Renzo; Osta, Rosario; Navarro, Xavier

doi:10.1002/BRB3.104

Title

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

Author

Casas, Caty

Herrando-Grabulosa, Mireia

Manzano, Raquel

Mancuso, Renzo

Osta, Rosario

Navarro, Xavier

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.

Language

English

Source (journal)

Brain and behavior. - Hoboken, NJ, 2011, currens

Publication

Hoboken, NJ : John Wiley & Sons , 2013

ISSN

2162-3279

DOI

10.1002/BRB3.104

Volume/pages

3 :2 (2013) , p. 145-158