It’s all about balance: How the brain eliminates unwanted connections

April 20, 2021

Written by: Claudia Lopez-Lloreda

Our brains contain billions of neurons and even more connections between them. Although these connections, called synapses, are critical for brain function, too many of them can be a problem. Networks in the brain are carefully crafted and they require a precise balance between neurons and connections. However, we are born with a surplus of neurons that then form many more connections than we actually need. So unwanted connections need to be removed in order to have appropriate brain function. 

The removal of unneeded connections occurs during development, in which a process called synaptic pruning happens1. Synaptic pruning is sort of like trimming a tree or cutting down overgrown hedges. In the brain, this elimination process leads to a dramatic reduction of connections during adolescence. The number of connections eventually stabilizes in adulthood and solidifies the functional networks needed for proper brain function. 

This synaptic refinement plays a role in normal brain functioning. Studies have found that networks function much better when pruning occurs3. Defects in synaptic pruning are associated with many conditions including autism and schizophrenia. For example, in schizophrenia, there is excess synaptic pruning, which leads to fewer synapses than normal2. This demonstrates that synaptic pruning may play a critical role in the emergence of developmental conditions, highlighting the importance of this process even without any neurological condition.

In order to prune synapses to achieve the correct level for healthy brain development, the brain has different strategies to calculate which connections it wants to get rid of. One of these strategies tracks which neurons or connections are active and which are inactive. Those that are active receive a “strengthening” signal, telling the connection to strengthen and survive, while inactive synapses receive an “elimination signal” that tells the brain to get rid of that connection. Some of the strengthening signals, such as proteins from the immune system called complement proteins, have already been identified. However, elimination signals have been less studied than their strengthening counterparts.

To examine these elimination signals, researchers at Harvard Medical School looked at what happened if they altered strength of connections in a bundle of axons called the corpus callosum, which connects the left and right hemispheres of the brain4. They expressed a protein that inhibits the transmission between synapses, in effect rendering that connection inactive. By artificially inducing inactivity, they found that many more connections were eliminated than normal, suggesting that inactivity led to an elimination process. 

Next, they screened to see which molecules were critical in this elimination process. They focused on a type of protein called protein tyrosine kinases since these had been shown to be critical for different aspects of synapse formation, including axon growth and regeneration. 

They then made versions of these proteins that were not functional and expressed them in the brain. They found that if they interfered with the function of one of these specific proteins, called JAK2, the connections that had been artificially induced to be inactive were no longer eliminated like they should have been. This indicated to the researchers that this protein was necessary in the process of removing unwanted synapses, pointing to the idea that JAK2 could be a potential elimination signal. 

Delving deeper into JAK2’s role, they saw that it was activated only in neurons that were inactive. Interestingly, they found that it was activated only in the presence of other connections that were activated, suggesting that active synapses send the elimination signal to nearby synapses that are inactive to induce removal. 

Then, instead of blocking JAK2, the researchers wanted to see what would happen if they increased its activity. They found that constant activation of JAK2 led to the elimination of synapses, even if they were active and not supposed to be removed. 

Finally, they wanted to determine JAK2’s role in the normal synaptic refinement that was occurring during development of the brain, not in their artificially induced system. Normally, connections are refined during the adolescent period of mice, a process that is dependent on neuronal activity. When they blocked the activity of JAK2, they found that the normal refinement process didn’t occur, leading to an excess of connections across the corpus callosum. This finding was also seen in other areas of the brain, suggesting that it could be a general elimination signal in the brain. Identifying these elimination signals is critical because it establishes a path to understanding the process of synaptic pruning. If researchers figure out the way the brain normally eliminates or keeps connections, they could leverage that knowledge to develop therapeutics for conditions that are characterized by synaptic pruning deficits. For example, they could study whether JAK2 is overactivated in schizophrenia, which would determine whether this protein is contributing to the development of the disease. Eventually, researchers could develop drugs to block JAK2, in hopes of restoring the balance between eliminating and preserving connections. 

Images

Cover image. Via Wikimedia Commons.

References

  1. Sakai, J. (2020). Core Concept: How synaptic pruning shapes neural wiring during development and, possibly, in disease. Proceedings of the National Academy of Sciences117(28), 16096–16099. https://doi.org/10.1073/pnas.2010281117
  2. Sellgren, C. M., Gracias, J., Watmuff, B., Biag, J. D., Thanos, J. M., Whittredge, P. B., … Perlis, R. H. (2019). Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nature Neuroscience22(3), 374–385. https://doi.org/10.1038/s41593-018-0334-7
  3. Navlakha, S., Barth, A. L., & Bar-Joseph, Z. (2015). Decreasing-rate pruning optimizes the construction of efficient and robust distributed networks. PLOS Computational Biology11(7). https://doi.org/10.1371/journal.pcbi.1004347

4. Yasuda, M., Nagappan-Chettiar, S., Johnson-Venkatesh, E. M., & Umemori, H. (2021). An activity-dependent determinant of synapse elimination in the mammalian brain. Neuronhttps://doi.org/10.1016/j.neuron.2021.03.006

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