New study shows how neural connections in the brain are formed
For neurons in the brain to form new connections with each other, the protein liprin-alpha must dock with receptors such as neurexin. These are the findings of a study conducted at the University of Gothenburg. This is a fundamental discovery about how the brain works, which could ultimately have implications for diseases such as autism and schizophrenia.
The results are published in the journal Nature Neuroscience. The research was conducted with international collaboration, in particular with a laboratory at Heidelberg University in Germany.
A synapse is the place where a neuron is in contact with another cell. These points of contact between neurons enable the flow of information in the brain where our thoughts, actions and emotions occur. The brain forms new synapses throughout life, and removes synapses that are no longer needed, probably to enable learning and long-term memory.
Human cultured neurons
The formation of synapses is controlled by signals via receiver proteins (so-called receptors) on the surface of neurons. One such receptor is neurexin. Scientists have long tried to figure out exactly how new synapses are formed, but it has proved difficult to pinpoint specific steps in the process. The role of neurexin, for example, has been debated as previous studies have produced contradictory results.
The first author is Berta Marco de la Cruz, PhD student at the Institute of Biomedicine. She has developed a new model system that combines cultured human neurons with the CRISPR genetic scissors. With support from CCI Core Facilities, she then studied the cells with advanced microscopy.
“The model system allows us to reconstruct synapses in genetically modified human neurons. We have shown how receptor proteins on the surface of neurons contribute to the formation of a synapse when two neurons meet,” says Berta Marco de la Cruz.
Genetically blocked synapse formation
The research collaboration has been led by Fredrik Sterky, Associate Professor at the Institute of Biomedicine, affiliated with the Wallenberg Center for Molecular and Translational Medicine (WCMTM):
“As far as we know, this is the first time anyone has succeeded in blocking the formation of structural synapses by genetic methods,” says Fredrik Sterky, and he continues:
“While neurexin and other receptor proteins are known to play a role, it has not previously been possible to show that neurexin is required to initiate the process of synapse formation, and not just to later define its properties. It is also not been known how such receptors trigger processes on the inside of the cell membrane for synapse formation to initiate.”
A chain of signals
The study identifies a protein family called liprin-alpha as necessary for human neurons to form new synapses. When the researchers removed all forms of liprin-alpha in human neurons, the neurons could no longer form structural and functional synapses. Through further studies, the researchers were able to show that either neurexin or its partner (a family of receptors called LAR-RPTPs) is needed to recruit liprin-alpha to the site of synapse formation. This shows that these receptor proteins are needed to form the synapse and to define its properties.
Malfunctioning synapses contribute to various psychiatric and neuropsychiatric conditions. One of the genes encoding the receptor protein neurexin is a well-known genetic risk factor for both schizophrenia and autism. Loss of synapses is also thought to underlie symptoms in neurodegenerative diseases such as Parkinson's and Alzheimer's. Understanding the function of the protein can provide insights into how these diseases occur.
“Simply put, autism is thought to result from impaired synapse formation, while schizophrenia is hypothesized to result from excessive breakdown of synapses. Our model supports these hypotheses,” says Fredrik Sterky.
The researchers are now using the model system to identify factors that may stabilize newly formed synapses. The aim is for the system to contribute to new treatments that could protect sensitive synapses in different disease states, such as schizophrenia.
TEXT: Elin Lindström
Article: Liprin-α proteins are master regulators of human presynapse assembly; https://www.nature.com/articles/s41593-024-01592-9