Degeneration of upper and lower motor neurons in a novel CSF-mediated animal model of sporadic ALS

Objective:

To determine whether intrathecal delivery of sporadic amyotrophic lateral sclerosis (sALS) cerebrospinal fluid (CSF) into the cervical subarachnoid space in mice can induce widespread degeneration of upper and lower motor neurons.

Background:

ALS is a neurodegenerative disease characterized by motor neuron loss throughout the CNS. We previously described how an intrathecal injection of sALS CSF into the cervical subarachnoid space of mice induces forelimb motor disability and motor neuron loss in the cervical spinal cord. This study focused on whether these neurodegenerative effects could also be seen in the motor cortices of sALS CSF-injected mice.

Design/Methods:

C57BL/6J mice underwent a laminectomy at vertebrae C4 and C5 before receiving an injection in the subarachnoid space of 3 uL of either saline or CSF obtained from sALS patients. Mice were perfused 1 day post-injection following evaluation of forelimb motor function. Spinal cords and brains were immunostained for either ChAT or NeuN, respectively. Numbers of ChAT⁺ lower motor neurons in the cervical and thoracic spinal cord, and NeuN⁺ upper motor neurons in the motor cortex were quantified.

Results:

The loss of lower motor neurons observed in the cervical spinal cord in our previous studies was also observed in the thoracic region, as indicated by significantly fewer ChAT⁺ motor neurons in sALS CSF-injected mice compared to saline controls. In the motor cortices, there was also a significant reduction in the number of NeuN⁺ upper motor neurons  following sALS CSF injection, demonstrating that sALS CSF delivered into the cervical subarachnoid space has widespread neurotoxic effects which correlate to impairments in forelimb function.  

Conclusions:

Neurotoxic factors in sALS CSF induce extensive motor neuron loss in the brain, cervical and thoracic spinal cord, providing further validation for the use of intrathecal sALS CSF injections into the cervical subarachnoid space as a new murine model for sALS.