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

Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
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
145-158
Casas, C.
ad5f1473-504c-47b2-8de7-83821827f693
Herrando-Grabulosa, M.
12dd4357-06ba-45b1-9ffd-478b6e8e31c2
Manzano, R.
8eb3064e-7775-424a-a755-542d8edc6a99
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Osta, R.
86d1bc86-c43c-41e4-8fde-a1e0758ff737
Navarro, X.
e02f3576-d8d3-495f-ba77-37e4f8769974
Casas, C.
ad5f1473-504c-47b2-8de7-83821827f693
Herrando-Grabulosa, M.
12dd4357-06ba-45b1-9ffd-478b6e8e31c2
Manzano, R.
8eb3064e-7775-424a-a755-542d8edc6a99
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Osta, R.
86d1bc86-c43c-41e4-8fde-a1e0758ff737
Navarro, X.
e02f3576-d8d3-495f-ba77-37e4f8769974

Casas, C., Herrando-Grabulosa, M., Manzano, R., Mancuso, Renzo, Osta, R. and Navarro, X. (2013) Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis. Brain and Behavior, 3 (2), 145-158. (doi:10.1002/brb3.104). (PMID:23531559)

Record type: Article

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

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Accepted/In Press date: 9 October 2012
e-pub ahead of print date: 17 February 2013
Organisations: Centre for Biological Sciences

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Local EPrints ID: 376108
URI: https://eprints.soton.ac.uk/id/eprint/376108
PURE UUID: c44d2c2c-5fcc-42c5-acde-78c793bc2033

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Date deposited: 27 Apr 2015 08:32
Last modified: 30 Jul 2019 18:39

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