Scientists from the University of Chicago studying pairs of neurons that innervate distinct muscles in a fruit fly model found that some neurons compensate for the loss of a neighboring partner. They say their study “Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit” published in the Journal of Neuroscience, represents 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 neurological diseases.
“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,” write the investigators.
“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.
“Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states.”
“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.
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?
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 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 neurodegenerative diseases like amyotrophic lateral sclerosis, which causes progressive neuron death and loss of muscle function, could show synaptic plasticity, according to the researchers.
The team now is 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.
