Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1 ^G86R and Fus ^{Δ NLS/+} ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1 ^G93A and Fus ^{Δ NLS/+} mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Abstract

Cortical dysfunction in ALS manifests in altered theta-gamma coupling that correlates with disease progression and relies on noradrenergic deficits.

Editor’s summary

Cortical hyperexcitability in amyotrophic lateral sclerosis (ALS) is commonly assessed by transcranial magnetic stimulation combined with electromyogram recordings, but this approach requires functional nerve-to-muscle connections. Scekic-Zahirovic et al. show that cortical hyperexcitability was associated with early deficits in theta-gamma phase-amplitude coupling (PAC) and decreased noradrenaline (NA) in the motor cortex of patients with ALS and mouse models. PAC deficits could be ameliorated by administration of a synthetic NA precursor in mice. These results suggest that PAC could serve as an alternative, muscle-independent readout for cortical hyperexcitability in ALS and warrant further studies into NA signaling as a potential molecular culprit driving this hyperexcitability. —Daniela Neuhofer