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.

Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis

“…Layer 5 pyramidal neurons in the motor cortex of a hTDP43 mouse model and corticospinal and cortico-cortico projection neurons in the motor cortex of SOD1 G93A mice display hyperexcitability [65,66]. In addition, a recent study using SOD1 G86R and FUS1 ∆NLS/+ mouse models described increased susceptibility to pentylenetetrazol, a GABA A receptor antagonist [67] that unravels network hyperexcitability, indicative of cortical network hyperexcitability in these models.…”

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

“…Thus, the research efforts were initially focused on MN and enabled the uncovering of different intrinsic pathological mechanisms. ALS appears to be caused by changes in excitability in multiple neuronal populations, including MNs (Benedetti et al, 2016 ; Chenji et al, 2016 ; Kim et al, 2017 ; Scekic-Zahirovic et al, 2024 ), which are caused by or associated with a variety of perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions, among others (Srinivasan and Rajasekaran, 2020 ). However, although the neuronal expression of mutated genes associated with fALS forms is sufficient to induce symptoms related to ALS (Jaarsma et al, 2008 ; Wang et al, 2009 ; Huang et al, 2012 ; Sharma et al, 2016 ), experimental evidence rapidly demonstrated the involvement of other cell types through non-cell autonomous mechanisms (reviewed in Crabe et al, 2020 ; Srinivasan and Rajasekaran, 2020 ; Van Harten et al, 2021 ).…”