Why inactive synapses are "annoying"? Scientists reveal the "punishment" mechanism of synapse pruning

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Forming proper synaptic connections is essential for the normal function of the brain.

There is an activity-dependent synapse pruning process in the brain: neurons selectively stabilize active synapses and eliminate inactive synapses.

Inactive synaptic connections will only be eliminated when there are other active connections competing with them.

But when all synaptic connections are not active, synaptic pruning may not happen.

This indicates that the active connection sends a "punishment" signal to the inactive connection, inducing the "elimination signal" to clean up the inactive synapse.

On March 27, 2021, Hisashi Umemori's research group at Boston Children's Hospital of Harvard Medical School revealed that the tyrosine kinase JAK2 signal can be used as an ``elimination signal'' to clear inactive synapses.

Establish an activity-dependent synaptic pruning model.
Because the corpus callosum is the largest axon bundle in the brain, it connects the two cerebral hemispheres and transmits motor, sensory and cognitive information.

Therefore, the researchers used the corpus callosum connection as a model for studying active synaptic pruning.
By implanting the tetanus toxin light chain (TTLC) into the corpus callosum by electrotransformation, the neurons in this area became competitive (about 80% of them were Active neurons, 20% are inactive neurons).

Under normal development, the projection density of corpus callosum axons increases from day 0 (P0) to day 5 (P5) after birth, decreases gradually from P5 to P15, and then tends to balance.

This indicates that the period from P5 to P15 is a critical period for axon pruning.

After electroporation of TTLC, active neurons in this area compete with inactive neurons, and then the axon density of neurons expressed by TTLC is significantly reduced, and some axons survive until adulthood, which indicates inactive synapses Can be selectively removed.

Tetrodotoxin inhibits neurons to cancel the effect of TTLC in reducing axon density.
In order to further verify the importance of neuronal activity for axon pruning, the researchers further injected tetrodotoxin (TTX) to achieve overall inhibition of neurons in the corpus callosum brain area.
, Which means that there is no active and inactive competition in this area.
Under this background, the phenomenon of axon density reduction caused by TTLC no longer exists.

Non-receptor protein tyrosine kinases (PTKs, including JAK2, JAK1, CSK, Fyn) play a key role in the regulation of axon growth, axon differentiation and axon regeneration.

The researchers constructed JAK2, JAK1, CSK, and Fyn mutants and transferred them to the corpus callosum together with TTLC.
They found that only the JAK2 mutants were transferred into the TTLC-expressing neuron axons that were not cleared.

Either exogenous or endogenous activation of JAK2 activity can promote axon clearance.

After inhibiting the activity of JAK2, it can effectively inhibit the clearance of axons, which indicates that JAK2 is necessary for the clearance of inactive axons.

What's more interesting is that the researchers found that JAK2 signal is rarely activated under normal conditions, but the activation of TTLC-inhibited neurons is increased, and after TTX inhibits the activity of all neurons, the activation of JAK2 is reduced.

This indicates that JAK2 signal is widely activated on inactive neurons only in the context of active-inactive competition.

Researchers injected AAV-Synaptophysin-mCherry virus into the corpus callosum, and found that the synaptic density was significantly reduced after JAK2 was activated, and the synaptic density was significantly increased after JAK2 was inhibited.

In general, this article found that JAK2 located at the presynapse can sense the "punishment" signal from the active synapse, and induce the inactive synapse to be cleared.

This activity-dependent synapse pruning method is actually the most economical: it is activated only when there is a competitive relationship; when everyone is not active, this method is hidden.

[References] 1.
https://doi.
org/10.
1016/j.
neuron.
2021.
03.
006 The pictures in the article are all from the references