ALS-FTD pathophysiology: treating the circuit behind the disease

About the project

Dysfunctional cortical inhibition, leading to excitotoxicity, has been previously reported in both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Our recent findings, obtained in a mouse model of ALS, showed also loss of inhibitory inputs in the spinal cord already during asymptomatic stages. Loss of inhibitory inputs can lead to aberrant neuron excitability, intracellular ion dysregulation and cell death, extensively reported in ALS-FTD. However, the exact role of dysfunctional inhibition in the onset and progression of the disease remains unclear. Our new preliminary data show that also excitatory interneurons are affected later in disease. Hence, we are currently investigating the exact temporal dynamics of inhibitory/excitatory interneuron degeneration in several mouse models of disease.

In ALS, main efforts have been directed to improve motor neuron survival and muscle reinnervation. However, we now know that loss of synapses happens not only in the peripheral nervous system, but also at central level. Thus, we investigated the effect of rescuing synaptic connectivity between interneurons and motor neurons. Here, we overexpressed the presynaptic protein Extended synaptotagmin 1 (Esyt1) known to promote neurotransmission and synaptic growth. Our study showed that stabilization of synapses by Esyt1 overexpression in inhibitory interneurons, leads to increased motor neuron survival and amelioration of motor phenotype. Thus, showing that interneurons can be a therapeutic target to reduce motor neuron loss and alleviate ALS symptoms.


Lundbeck Foundation


Allodi I, Montañana-Rosell R, Selvan R, Löw P, Kiehn O
Loss of V1 interneuron synaptic inputs onto fast fatigable motor neurons leads to gait impairment in a SOD1G93A mouse model
Nature Communications
2021 Mar 31
Allodi I, Nijssen J, Aguila Benitez J, Schweingruber C, Fuchs A, Bonvicini G, Cao M, Kiehn O, Hedlund E
Modeling motor neuron resilience in ALS using stem cells
Stem Cell Reports
2019 May 09

Primary location

St Andrews

Principal Investigator

Other people involved

Prof. Ole Kiehn, Prof. Joost Verhaagen, Dr. Susana Aznar