The Brain’s Immune Cells Help Motor Neurons Recover in a Mouse Model of ALS

What's the science?

ALS is a devastating disease where motor neurons degenerate. TDP-43 is a toxic protein that builds up in ALS and contributes to this degeneration. It is unclear whether the immune cells of the nervous system, microglia, react to TDP-43 and whether they play a protective role or make neurodegeneration worse. This week in Nature Neuroscience, Spiller and colleagues test whether microglia contribute to neurodegeneration in a mouse model of ALS.

How did they do it?

They used a transgenic mouse model for ALS in which TDP-43 (toxic protein) build-up can be induced or reversed by suppressing or activating TDP-43 gene expression. With this model they can simulate motor neuron degeneration or recovery. The authors measured whether there were any changes in the number of microglia or their activation state (indicated by the size and shape of the cells) at several time points using immunostaining in the spinal cord, both after inducing TDP-43 damage and after reversing this process. Increases in microglia number and activation indicate that the microglia are actively responding to neuron damage. They also measured gene expression changes in the microglia during the degeneration and recovery of motor neurons. They then measured whether TDP-43 could be found inside the microglial cells, indicating that the microglia are “eating” the proteins to clear them. Finally, they blocked microglia cell replication to test how motor neuron function would recover in regenerating motor neurons.

What did they find?

Microglia were not initially reactive to toxic protein buildup. By the time the motor neurons were severely degenerated, there was a slight increase in the number of microglia and a change in the activation state (i.e. the number of microglia reacting). After reversing the TDP-43 pathology, microglia number and activation increased immediately and dramatically, suggesting that the microglia play a more important role in helping motor neurons recover. This activation of microglia was specific to TDP-43 proteins, and not just a response to neuron death in general. The microglia also showed many changes in gene expression during early recovery (and not early disease), indicating that they are involved in the early recovery process. TDP-43 was found inside microglia, showing that these immune cells actually clear TDP-43 during recovery. When microglial cells were not able to multiply, the motor neurons that were damaged by TDP-43 did not fully recover, and the mouse did not regain full motor function, indicating that microglia are required for a full motor recovery.

                                Microglia,  S  ervier Medical Art,  image by BrainPost,  CC BY-SA 3.0

                                Microglia, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to show that microglia are involved in the recovery of motor neurons in a reversible mouse model of ALS. Previously, we weren’t sure whether these immune cells of the nervous system actually make things worse or protect neurons from damage in ALS. We now know that microglia play an active role in restoring motor function in neurons damaged by TDP-43 protein buildup in this mouse model of ALS. Currently, we do not have therapies to restore motor function in ALS, and this study suggests that we may be able to target microglia.

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Reach out to study author Dr. Krista Spiller on Twitter @krista_spiller

K. Spiller et al., Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nature Neuroscience (2018). Access the original scientific publication here.

Ketamine Blocks Burst Firing to Provide Depression Relief

What's the science?

Ketamine is a drug that binds to and blocks NMDA receptors found on neurons. It provides fast acting and sustained relief of depression symptoms, however, the mechanisms underlying ketamine’s effectiveness are unknown. A brain region called the lateral habenula, involved in reward processing and negative emotions, is known to have abnormal “burst” activity in patients with depression. This week in Nature, Yang and colleagues determine whether abnormal activity in the lateral habenula can drive depression-like behaviours, and how this might be reversed by ketamine.

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How did they do it?

They tested to see if ketamine infusion into the lateral habenula relieved depression symptoms (improved mobility in the forced swim test) in learned helpless (depressed) rats. Next, they performed whole-cell patch-clamp (a method used to measure the electrical currents in a neuron) on lateral habenula neurons to determine : 1) whether the spontaneous neuronal activity in these cells is abnormal in depressed rats, 2) whether these abnormalities could be reversed by NMDA blockers and, 3) if changing the resting state membrane potential of the cell can alter the pattern of spiking activity in the lateral habenula. They then used optogenetic techniques to mimic the bursting activity seen in the lateral habenula of depressed mice to determine whether this activity was sufficient to induce depression behaviours.

What did they find?

Ketamine administered in the lateral habenula alleviated the depression symptoms in rats. Increased burst firing occurred in neurons in the lateral habenula of depressed rats. These burst patterns were completely blocked by ketamine, but not by other typically used antidepressant drugs. The bursting properties of the lateral habenula could be altered by changing the membrane potential of the cell, suggesting a new potential therapeutic target, the T-type calcium channel. They were also able to induce depression-like symptoms in rats by using optogenetics to control the pattern of burst firing in the lateral habenula.

What's the impact?

This is the first study to describe the mechanisms by which ketamine has fast acting depression relief. We now know that burst firing underlies depressive symptoms in rats, and that this can be blocked with ketamine. Understanding how and where ketamine acts in the brain is an important step towards developing new therapies for depression.  

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Yang et al., Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. (2018). Access the original scientific publication here.

Rachel Bosma, PhD contributed to this BrainPost