ALS: Missing neuromodulator triggers hyperexcitability in the cerebral cortex

March 27, 2024

A new study led by BMC researcher Sabine Liebscher together with French research teams unravels a key role of the neuromodulator noradrenaline in pathological neuronal activity patterns in cortex of ALS patients.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, characterized by the loss of upper and lower motor neurons in cortex and the spinal cord, respectively. Despite decades of research and valuable insight into the molecular mechanisms driving motor neuron degeneration the disease still remains incurable and treatment options have a very limited impact on disease progression. So far, research has strongly focused on the investigation of lower motor neuron death. Very little is known about upper motor neurons and the motor cortex in general, despite ample evidence for its crucial involvement in the initiation and progression of ALS pathophysiology. This is partly due to the fact that upper motor neuron dysfunction is difficult to assess in patients as the assessment hinges on intact neuron–muscle connections, which are destroyed in the disease.

In their new study the teams of Sabine Liebscher, Véronique Marchand-Pauvert and Caroline Rouaux have identified a new method to read-out cortical hyperexcitability in ALS patients and mouse models of the disease, which is based on the coupling of certain neuronal activity frequencies – called phase-amplitude coupling. This approach should now enable a faster diagnosis even when neuron–muscle connections are damaged. The German-French research teams aimed to understand the underlying mechanisms driving these pathological activity patterns in ALS. To this end, they investigated postmortem brain tissue from ALS patients and used several mouse models of ALS to gain insight into alterations affecting the neuronal circuits of the motor cortex. Their work unraveled that a deficit of the neuromodulator noradrenaline plays a key role in the observed cortical hyperexcitability. Pharmacological tests with already approved drugs demonstrate that noradrenergic deficiency can be restored and partially normalizes cortical hyperexcitability.

These new insights highlight the role of circuit mechanisms in ALS pathophysiology and now pave the way for novel therapeutic strategies to combat this devastating disease.

Publication: Scekic-Zahirovic et al.: Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficienc, Science Translational Medicine 2024