Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity in Neurodegenerative Disorders

Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity inNeurodegenerative Disorders

The processes leading to many neurodegenerative diseases remain unknown despite intense research scrutiny. For example, we still don’t know why, in some people, enough neural cells die to impair movement (in neuromuscular diseases such as amyotrophic lateral sclerosis (ALS)) and cognition (in neurodegenerative diseases such as Alzheimer’s and other dementias).

For some cases of ALS and dementias, however, the underlying genetic cause is known. For example, certain cases of ALS and a form of dementia known as frontotemporal dementia (FTD) are caused by mutations in a protein known as TAR DNA-binding protein 43 (TDP-43). A mouse model has been created to study how the over-expression of a mutant TDP-43 gene can lead to neurodegeneration and aspects of ALS and FTD pathology in the mice.

In work done largely at JAX, former JAX Assistant Professor Da-Ting Lin, Ph.D., who is now at the National Institutes of Health, led a team that used the TDP mice to investigate dysfunction of cortical inhibition, a phenotype observed in human ALS patients. If the balance between neuronal excitation and inhibition is disrupted, the neuron can fire far too often, leading to what’s known as excitotoxicity and eventually to cell death. In a paper published in Nature Neuroscience, the team, which also included current JAX faculty members Zhong-wei Zhang, Ph.D., and Greg Cox, Ph.D., shows that TDP mice do indeed have impaired inhibition in layer 5 pyramidal neurons (L5-PN), an important type of cortical neuron.

The researchers went further to find the source of the inhibition dysfunction. What they found was an upstream regulatory microcircuit gone awry. L5-PN depend on separate classes of interneurons to permit or inhibit neuron firing, and one type of these interneurons, somatostatin expressing, or Sst), was hyperactive in the TDP mice, while another (pervalbumin expressing, or Pv) was hypoactive. Through a series of experiments, Lin et al showed that Sst interneurons fire to inhibit Pv interneurons, preventing them from inhibiting the L5-PN. So if Sst interneurons are hyperactive, so are the L5-PN. To test this, the researchers were able to remove Sst interneurons from the brains of TDP mice and found that it eliminated the excitotoxicity/neurodegeneration phenotype within two weeks. Targeting this subpopulation of inhibitory interneurons may provide a new option for ALS/FTD therapy development.

Zhang, W et al. 2016. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nature Neuroscience. doi:10.1038/nn.4257