A New Clue for Treating Brain Disorders: Discovery of Context-Dependent Synapse Regulation Principles [Reading Science]

DGIST Research Team First to Demonstrate Circuit-Specific Roles of Slitrk Proteins

A new approach to treating brain disorders has emerged. A research team at Daegu Gyeongbuk Institute of Science and Technology (DGIST) has, for the first time in the world, discovered that synapses connecting brain neurons are precisely regulated by different molecular principles depending on the location in the brain and the micro-neural circuit environment. This finding raises hopes for a more precise understanding of intractable brain disorders such as autism and schizophrenia, and for the development of treatment strategies that target only the problematic synapses.

Mechanism and operational model by which excitatory synapse Slitrk paralog proteins regulate specific excitatory synapse properties according to hippocampal neural circuits. Provided by the research team

The Synapse Diversity and Specificity Control Research Group in the Department of Brain Sciences at DGIST announced that Slitrk proteins, which are involved in synapse formation, do not always perform the same function. Instead, they revealed the molecular mechanism by which these proteins play different roles and finely regulate synapse function depending on the context of the neural circuit and surrounding environment.

The human brain contains about 100 billion neurons connected by more than 100 trillion synapses. Such connections must be formed precisely for memory, learning, and behavior to occur. However, which molecules are responsible for creating these sophisticated connections had long remained unclear.

Distinct Roles of 'Sibling Proteins' in Each Hippocampal Microcircuit

Since 2013, the research team has been steadily studying the Slitrk family of synaptic adhesion proteins. In this study, they focused on Slitrk1 and Slitrk2, which are structurally very similar and were thought to have similar functions.

Using cutting-edge neuroscience techniques, the researchers precisely analyzed synaptic changes after individually removing the Slitrk1 and Slitrk2 genes in the mouse hippocampus. They found that the two proteins did not function identically; instead, each regulated different excitatory synapse properties in distinct microcircuits within the hippocampus. This demonstrates that the function of these proteins is not fixed, but rather changes depending on the molecular environment that interacts with the surrounding neural circuits.

From the left, Byungchan Kim, PhD candidate at DGIST, Dongwook Kim, PhD at DGIST, Jaewon Ko, Professor at DGIST. Provided by DGIST

In particular, the research team confirmed that the Slitrk2 gene mutation (V89M), previously reported in schizophrenia patients, also causes abnormal synaptic signaling and impaired spatial memory in animal models. This is considered experimental evidence showing how synapse-related genetic changes found in various neuropsychiatric disorders-such as autism, schizophrenia, and obsessive-compulsive disorder-lead to actual brain dysfunction.

The results of this study were published online on the 18th in the international journal "PLoS Biology" under the title "Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms."

Jaewon Ko, Professor of the Synapse Diversity and Specificity Control Research Group at DGIST, stated, "Just as siblings born to the same parents have different roles and personalities, brain proteins also exhibit different specializations depending on the neural circuit environment, finely tuning the neural circuits. This study presents a new principle and could be the starting point for understanding the causes of brain disorders that occur only in specific neural circuits, and for developing precision therapies that selectively target only the malfunctioning synapses."

This research was jointly conducted by Dongwook Kim and Jinhu Kim, PhDs at DGIST, and Byungchan Kim, researcher at DGIST, as co-first authors. Also participating were Professor Jiweon Um of DGIST, Dr. Gyeju Lee of the Korea Brain Research Institute, Professor Changho Son of the Graduate School of Medical Science and Engineering at KAIST, and Professor Joris de Wit of KU Leuven in Belgium. The study was supported by the Ministry of Science and ICT and the National Research Foundation of Korea's Global Leader Research Program, among others.