. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat Neurosci. 2016 Apr;19(4):557-9. Epub 2016 Feb 22 PubMed.


Please login to recommend the paper.


  1. This article addresses an important area of ALS research that has been relatively neglected. There is substantial clinical evidence that dysfunction of interneuron populations could be a potential contributor to upper motor neuron hyperexcitability in ALS, which has been known for nearly 20 years. This has been demonstrated using paired pulse transcranial magnetic stimulation (TMS) techniques. For example, reduced short-interval intracortical inhibition (SICI) has been demonstrated in sporadic ALS as well familial disease, and in familial disease it occurs early, before symptom onset (Grieve et al., 2015; Vucic et al., 2008). There have been few follow-up studies in animal models to dissect out mechanisms or try to determine if a specific type of interneuron is affected, but very little work has been done to dissect out mechanisms of hyperexcitability in TDP-43 models. It is exciting to see progress in this area. In terms of FTD the contribution of hyperexcitability is far less clear and less work has been done in this area.

    This paper examines hyperexcitability in a mutant TDP-43 mouse model. It identifies dysfunction in a specific class of interneurons that are classified by their expression of somatostatin. Signs of excitotoxic injury, such as dendritic blebbing were present in layer 5 pyramidal neurons from early timepoints. This paper is elegant in that it not only shows reduced inhibitory input acting through parvalbumin interneurons, but also that ablating somatostatin immunoreactive interneurons prevents subsequent pathology and neuronal loss. Unlike many studies in ALS research, this paper focuses on the motor cortex rather than the spinal cord. It is currently unclear if pathology is driven from upper or lower motor neurons or if both occur independently, although cortical hyperexcitability is demonstrated in clinical studies.

    It is of course too early to make conclusions about whether similar mechanisms are occurring in human ALS. Considerable work needs to be done here. In human tissue there have been few histological studies looking at interneurons, particularly in recent times, and findings are in some cases contradictory. It will be important to follow up this study by looking at whether mutated TDP-43 expression directed toward specific cell types, such as interneuron populations, can alone drive pathology. And, while the authors identified a GABAergic mechanism, it still needs to be determined if somatostatin plays a role. Additionally, studies will need to determine whether this mechanism is specific to mutant TDP-43. In this regard, studies in other models (such as G93A mSOD1) and in iPSCs have suggested increased excitability in motor/pyramidal neurons.

    In summary, this paper supports a growing body of evidence that targeting excitability in ALS is an important avenue to pursue and offers hope that modulation of inhibitory networks may be a potential therapeutic option for treatment of this disease.

    View all comments by Anna King
  2. This is a very exciting paper with remarkable implications. The key finding that alterations in somatostatin interneurons may be driving the degeneration of layer 5 cortical neurons is potentially paradigm-shifting. The authors were able to show that blocking the action of those inhibitory interneurons was sufficient to protect layer 5 cortical neurons from excitotoxic death. Further work will be needed to determine if a similar pathway occurs in other mouse models, and ultimately in humans where cortical hyperexcitability is also an early finding. But there is no doubt it brings to light that targeting specific interneuron populations may be therapeutically protective, a very exciting prospect.

    View all comments by Robert Baloh

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. A Cortical Neuron Circuit Overloads in ALS Model Mice

Research Models

  1. TARDBP (A315T) (congenic)