Scientists at the University of Montreal and its affiliated Montreal Clinical Research Institute (IRCM) have discovered unique roles for a protein complex in the structural organization and connectivity function of brain cells, as well as in cognitive behaviors specific.
The work of a team led by Hideto Takahashi, director of the plasticity and synapse development research unit at IRCM, in collaboration with Steven Connor’s team from the University of York and Masanori Tachikawa’s team from Tokushima University in Japan , is published in EMBO Magazine.
Although defects in the organization of synapses are related to many neuropsychiatric conditions, the mechanisms responsible for this organization are not well understood. The researchers believe the new study’s findings could provide valuable therapeutic insights.
It is important to keep two goals in mind with this research, said Takahashi, associate medical research professor in molecular biology and neuroscience at UdeM.
“One is to discover new molecular mechanisms for brain cell communication,” he said. “The other is to develop a new unique animal model of anxiety disorders that show behaviors similar to panic disorder and agoraphobia, which will help us develop new therapeutic strategies.”
Understand the mechanisms
Mental illnesses, such as anxiety disorders, autism and schizophrenia, are among the leading health disorders in Canada and around the world. Despite their prevalence, drug development and treatment of many of these diseases have proven to be very challenging due to the complexity of the brain. Therefore, scientists have strived to understand the underlying mechanisms that lead to cognitive disorders to advance therapeutic strategies.
The junctions between two brain cells (neurons) are called synapses and are essential for the transmission of neuronal signals and brain functions. Defects in excitatory synapses, which activate the transmission of signals to target neurons, and in synaptic molecules, predispose to many mental diseases.
Takahashi’s team previously discovered a new protein complex within the synaptic junction, called TrkC-PTPσ, that is only found at excitatory synapses. The genes encoding TrkC (NTRK3) and PTPσ (PTPRS) are associated with anxiety disorders and autism, respectively. However, the mechanisms by which this complex regulates synapse development and contributes to cognitive functions are unknown.
Work performed in the new study by first author Husam Khaled, a doctoral student in Takahashi’s laboratory, demonstrated that the TrkC-PTPσ complex regulates the structural and functional maturation of excitatory synapses by regulating phosphorylation, a biochemical modification of proteins, of many synaptic synapses. proteins, while disruption of this complex causes specific behavioral defects in mice.
Building blocks of the brain
Neurons are the basic components of the brain and nervous system that are responsible for sending and receiving signals that control brain and body functions. Neighboring neurons communicate through synapses, which act as bridges that allow signals to pass between them.
This process is essential for proper brain functions, such as learning, memory, and cognition. Defects in synapses or their components can alter communication between neurons and cause various brain disorders.
By generating mice with specific genetic mutations that disrupt the TrkC-PTPσ complex, Takahashi’s team uncovered the unique functions of this complex. They showed that this complex regulates the phosphorylation of many proteins involved in the structure and organization of synapses.
High-resolution images of the brains of the mutant mice revealed abnormal synapse organization, and further studies of their signaling properties showed an increase in inactive synapses with defects in signal transmission. By observing the behavior of the mutant mice, the scientists saw that they exhibited elevated levels of anxiety, especially increased avoidance in unfamiliar conditions and impaired social behaviors.