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

Brain and Behavior, 2013 · DOI: 10.1002/brb3.104 · Published: March 1, 2013

Simple Explanation

This study investigates the early changes in the cholinergic system in a mouse model of ALS before the onset of motor symptoms. It focuses on choline acetyltransferase (ChAT), an enzyme crucial for producing acetylcholine, a neurotransmitter. The research reveals that even before the mice show any signs of motor neuron degeneration, there's a reduction in ChAT content in the spinal cord, particularly in motor neurons and interneurons. These early cholinergic dysfunctions are concurrent with other pathological changes, such as Tdp-43 accumulation and mild oxidative stress, suggesting they might be early drivers of ALS pathogenesis.

Study Duration

3 Months

Participants

SOD1G93A mice and wild-type littermates

Evidence Level

Level 3, Animal study

Key Findings

1
An early reduction in ChAT content was observed in the soma and presynaptic boutons of motor neurons, as well as in cholinergic interneurons in the lumbar spinal cord of 30-day-old SOD1G93A mice.
2
Cholinergic synaptic stripping occurred simultaneously with the presence of MHC-II-positive microglia and the accumulation of nuclear Tdp-43, along with mild oxidative stress within motor neurons.
3
Alterations in postsynaptic cholinergic-related structures were revealed, including a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone, in the postsynaptic cisternae.

Research Summary

The study demonstrates early cholinergic dysfunction in the spinal cord of SOD1G93A mice, an ALS model, preceding motor neuron loss. This dysfunction manifests as reduced ChAT content in motor neurons and interneurons. This early cholinergic impairment is associated with synaptic stripping, microglial activation, Tdp-43 accumulation, and oxidative stress, suggesting a complex interplay of pathological processes in early ALS. The findings suggest that cholinergic dysfunction may be a crucial early event in ALS etiopathogenesis, potentially affecting motor neuron excitability and vulnerability to excitotoxicity.

Practical Implications

Early Diagnostic Potential

Electrophysiological studies focusing on repetitive nerve stimulation and recurrent inhibition should be considered for early ALS diagnosis in patients.

Therapeutic Target

ChAT production and function could be potential therapeutic targets for ALS treatment.

Understanding ALS Etiopathogenesis

Further investigation of the relationship between mild oxidative stress, Tdp-43 expression, and ChAT downregulation may provide insight into the early mechanisms of ALS.

Study Limitations

1
The study is limited to a mouse model of ALS, and the findings may not directly translate to human ALS.
2
The exact mechanisms linking cholinergic dysfunction to other pathological events like Tdp-43 accumulation and oxidative stress require further investigation.
3
The study focuses primarily on the spinal cord, and the role of cholinergic dysfunction in other brain regions affected by ALS remains unclear.

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