Dendritic tree pruning | Mirage News
Researchers at the University of Bonn have shed light on the function of the enzyme SLK for the development of nerve cells in the brain. If it is missing, the branches of neurons are less abundant. In addition, it is then more difficult to inhibit the activity of the cells. This is consistent with the fact that there is less SLK in diseased brain tissue in patients with epilepsy. Epileptic seizures are characterized by overexcitation of clusters of neurons. The results may help improve treatment for the disease. The study is published in the Journal of Neuroscience.
SLK belongs to the large group of kinases. These enzymes are extremely important: they attach phosphate groups (which are small molecular residues with a phosphorus atom in the center) to proteins and thereby alter their activity. Kinases are involved in the regulation of almost all life processes in animals.
The SLK kinase was already known to play an important role in embryonic development: one of its effects is on the growth of cells and their migration in the organism; these processes are also essential for the maturation of neurons. “We therefore studied the function that SLK performs in nerve cells,” explains Prof. Albert Becker from the Institute of Neuropathology at the University of Bonn.
The researchers inhibited the production of the SLK protein in mouse neurons. “It changed the appearance of neurons”, explains Anne Quatraccioni, who is doing her doctorate at the Institute of Neuropathology in the research group of Professor Dr. Susanne Schoch McGovern: “The dendrites, which are the extensions that receive signals other neurons and lead them to the less branched cell body.
SLK deficiency makes neurons more excitable
Dendrites look like a kind of tree with tiny points of contact, called synapses. This is where extensions of other nerve cells dock and transmit electrical impulses to the tree. The observed thinning did not affect the thick main branches, but only the smaller shoots. The synapses on these small branches are called exciters: the signals received there have an excitatory effect. This means that they increase the probability that the neuron in turn generates an electrical signal, in other words, that it “goes off”.
When there are fewer side branches, the synapses could concentrate in a smaller area and thus gain influence, making the neuron easier to excite (since synapses are excitatory). “Surprisingly, however, we did not find an increased density of excitatory synapses,” Quatraccioni points out. “However, the affected neurons were more excitable. But there had to be other reasons.
The cause is not to be found in the delicate branches, but in the thick main branches. Many synapses are also located there, but of a different type: they have an inhibitory effect. Any signal received by these synapses prevents the nerve cell from triggering. “The mice initially formed a normal amount of these inhibitory synapses,” Quatraccioni explains. “However, after a few days of life, their density started to decrease. This loss continued to increase.
SLK therefore appears to be important in maintaining normal levels of inhibitory synapses. Without the kinase, affected neurons become increasingly difficult to inhibit over time. This is consistent with the fact that researchers were able to detect SLK deficiency in nerve cells in brain tissue of patients with epilepsy. During epileptic seizures, entire areas of the brain are overexcited, which means that neurons fire too easily.
Explanation of the decrease in the effectiveness of the drug?
The results could also explain why the effects of the drugs wane over time in some people with the condition. “Perhaps this effect is not due to drug resistance, but to the gradual loss of inhibitory synapses,” says Professor Susanne Schoch McGovern. The results therefore provide new information on how the disease develops.
They could also have therapeutic relevance: “We often try to prevent neuronal overexcitation with drugs that stimulate inhibitory synapses,” says Schoch McGovern. “This could be the wrong strategy in the case of SLK deficiency: at some point there are so few inhibitory synapses left that it no longer works. It is probably more promising in these patients to intervene on the excitatory side, that is, to inhibit the excitatory synapses.
- Susanne Schoch, Anne Quatraccioni, Barbara K. Robens, Robert Maresch, Karen MJ van Loo, Silvia Cases-Cunillera, Tony Kelly, Thoralf Opitz, Valeri Borger, Dirk Dietrich, Julika Pitsch, Heinz Beck, Albert J. Becker. The Ste20-like kinase is essential for the maintenance of the inhibitory synapse and its deficiency confers developmental dendritopathy. The Journal of Neuroscience, 2021; 41 (39): 8111 DOI: 10.1523 / JNEUROSCI.0352-21.2021