Summary: Some neurons have the ability to detect and compensate for neighboring neurons, while others do not. The findings shed new light on synaptic plasticity.
Source: University of Chicago
Our brains are complicated webs of billions of neurons, constantly transmitting information across synapses, and this communication underlies our every thought and movement.
But what happens to the circuit when a neuron dies? Can other neurons around it pick up the slack to maintain the same level of function?
Indeed they can, but not all neurons have this capacity, according to new research from the University of Chicago. By studying several neuron pairs that innervate distinct muscles in a fruit fly model, researchers found that some neurons compensate for the loss of a neighboring partner.
The results, published February 17, 2021, in the Journal of Neuroscience, are a step in the direction of understanding the plasticity of the brain and using that knowledge to better understand not only normal development, but also neurodegenerative diseases.
“Now that we know that some neurons can compensate when other neurons die, we can ask whether this process can also happen in neurological diseases,” said Robert Carrillo, PhD, assistant professor of Molecular Genetics and Cell Biology and corresponding author of the paper.
Because the human brain is incredibly complex, researchers use the comparatively simple fruit fly model to investigate fundamental neuroscience concepts that could potentially translate to our higher-order brains.
To better understand how the brain adapts to structural and functional changes, Carrillo and graduate student Yupu Wang examined the fruit fly’s neuromuscular system, where each muscle is innervated by two motor neurons. While it is known that neurons can alter their activity when perturbations happen at their own synapses, a process known as synaptic plasticity, they wondered what would happen if one neuron was removed from the system. Would the other neurons respond and compensate for this loss?
It’s not an easy question to answer: Removing single neurons without simultaneously destroying other neurons is difficult, and it is also difficult to measure a single neuron’s baseline activity. The researchers solved this by expressing cell death-promoting genes in a very specific subset of motor neurons. They then used imaging and electrophysiological recordings to isolate the activity of the single remaining neuron in the pair.
In one muscle, they found that the remaining neuron expanded its synaptic arbor and compensated for both the spontaneous and evoked neurotransmission of its missing neighbor. When the researchers performed the same procedure on two other muscles, however, they found that the remaining neuron did not compensate for the loss of its neighbor.
“It appears that some neurons have the ability to detect and compensate for their neighboring neuron, and others do not,” said Wang, who is doing his graduate studies in the Committee on Development, Regeneration and Stem Cell Biology.
That could be because, as the researchers found, each neuron has different functional properties. The neuron that compensated for the loss of its neighbor also contributed most to the overall activity of the muscle under baseline conditions.
This still left the researchers with an intriguing question: How does the remaining neuron know how much to compensate? They hypothesized that the neuron pairs work together to establish a “set point” for activity upon circuit formation. Indeed, they found that if the neuron’s neighbor never forms synapses – if the system never knew it was supposed to get information from two neurons – then the remaining neuron will not compensate.
That leaves hope that further studies could help illuminate whether neurons whose neighbors are affected by neurogenerative diseases like amyotrophic lateral sclerosis (ALS), which causes progressive neuron death and loss of muscle function, could show synaptic plasticity.
Next the researchers are studying the mechanism that causes the compensation. They hope to better understand how the signal that the neuron has died is sent, and how that signal in turn causes the other neuron to compensate.
Funding: The study, “Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit,” was supported by National Institutes of Health grants K01-NS-102342 and T32-GM-007183, the University of Chicago Biological Sciences Division, and the Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior. Additional authors include Meike Lobb-Rabe, James Ashley and Veera Anand.
About this synaptic plasticity research news
Source: University of Chicago
Contact: Alison Caldwell – University of Chicago
Image: The image is credited to Robert Carrillo, PhD, and Yupu Wang
Original Research: Closed access.
“Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit” by Yupu Wang, Meike Lobb-Rabe, James Ashley, Veera Anand and Robert A. Carrillo. Journal of Neuroscience
Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit
Throughout the nervous system, the convergence of two or more presynaptic inputs on a target cell is commonly observed. The question we ask here is to what extent converging inputs influence each other’s structural and functional synaptic plasticity. In complex circuits, isolating individual inputs is difficult because postsynaptic cells can receive thousands of inputs.
An ideal model to address this question is the Drosophila larval neuromuscular junction (NMJ) where each postsynaptic muscle cell receives inputs from two glutamatergic types of motor neurons (MNs), known as 1b and 1s MNs. Notably, each muscle is unique and receives input from a different combination of 1b and 1s MNs; we surveyed multiple muscles for this reason.
Here, we identified a cell-specific promoter that allows ablation of 1s MNs postinnervation and measured structural and functional responses of convergent 1b NMJs using microscopy and electrophysiology.
For all muscles examined in both sexes, ablation of 1s MNs resulted in NMJ expansion and increased spontaneous neurotransmitter release at corresponding 1b NMJs. This demonstrates that 1b NMJs can compensate for the loss of convergent 1s MNs. However, only a subset of 1b NMJs showed compensatory evoked neurotransmission, suggesting target-specific plasticity. Silencing 1s MNs led to similar plasticity at 1b NMJs, suggesting that evoked neurotransmission from 1s MNs contributes to 1b synaptic plasticity.
Finally, we genetically blocked 1s innervation in male larvae and robust 1b synaptic plasticity was eliminated, raising the possibility that 1s NMJ formation is required to set up a reference for subsequent synaptic perturbations.
In complex neural circuits, multiple convergent inputs contribute to the activity of the target cell, but whether synaptic plasticity exists among these inputs has not been thoroughly explored. In this study, we examined synaptic plasticity in the structurally and functionally tractable Drosophila larval neuromuscular system. In this convergent circuit, each muscle is innervated by a unique pair of motor neurons. Removal of one neuron after innervation causes the adjacent neuron to increase neuromuscular junction outgrowth and functional output.
However, this is not a general feature as each motor neuron differentially compensates. Further, robust compensation requires initial coinnervation by both neurons. Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states.