Scientists have found that a specific protein complex significantly influences brain connectivity and cognitive behaviors.
Their studies on mice revealed that disruptions in this complex affect synapse formation and lead to behavioral changes, such as increased anxiety and impaired social interactions, pointing toward new treatment possibilities for mental health conditions.
Protein Complex Roles in Brain Connectivity
Researchers at the Université de Montréal and the Montreal Clinical Research Institute (IRCM) have discovered important functions of a protein complex in shaping the structure and function of brain cell connections and influencing certain cognitive behaviors.
The study, led by Hideto Takahashi, director of the IRCM’s synapse development and plasticity research unit, in collaboration with teams from York University led by Steven Connor and Tokushima University led by Masanori Tachikawa, has been published in The EMBO Journal.
Investigating Synapse Organization and Cognitive Behaviors
The research addresses how disruptions in the organization of synapses—the junctions between brain cells—are connected to various neuropsychiatric disorders, an area that has remained largely unexplained. The team’s findings offer promising leads for developing new therapeutic approaches.
Two goals are important to bear in mind with this research, said Takahashi, an associate research medical professor in molecular biology and neuroscience at UdeM.
“One is to uncover novel molecular mechanisms for brain cell communication,” he said. “The other is to develop a new unique animal model of anxiety disorders displaying panic disorder- and agoraphobia-like behaviors, which helps us develop new therapeutic strategies.”
Understanding the Underlying Mechanisms of Cognitive Disorders
Mental illnesses, such as anxiety disorders, autism and schizophrenia are among the leading health disorders in Canada and worldwide. Despite their prevalence, drug development and treatment for many of these illnesses have proven to be very challenging, due to the complexity of the brain. Scientists have therefore strived to understand the underlying mechanisms that lead to cognitive disorders in order to advance therapeutic strategies.
The junctions between two brain cells (neurons) are called synapses, which are essential for neuronal signal transmission and brain functions. Defects in excitatory synapses, which activate signal transmission to target neurons, and those in synaptic molecules predispose to many mental illnesses.
Exploring the Impact of the TrkC-PTPσ Protein Complex
Takahashi’s team has previously discovered a new protein complex within the synaptic junction, called TrkC-PTPσ, which is only found in excitatory synapses. The genes coding for 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.
The work carried out in the new study by first author Husam Khaled, a doctoral student in Takahashi’s laboratory, showed that the TrkC-PTPσ complex regulates the structural and functional maturation of excitatory synapses by regulating the phosphorylation, a biochemical protein modification, of many synaptic proteins, while disruption of this complex causes specific behavioral defects in mice.
Role of Neurons and Synapses in Brain Functions
Neurons are the building blocks of the brain and the nervous system that are responsible for sending and receiving signals that control the brain and body functions. Neighboring neurons communicate through synapses, which act like bridges that allow the passage of signals between them.
This process is essential for proper brain functions such as learning, memory, and cognition. Defects in synapses or their components can disrupt communication between neurons, and lead to various brain disorders.
Consequences of Genetic Mutations on Brain Behavior
By generating mice with specific genetic mutations that disrupt the TrkC-PTPσ complex, Takahashi’s team uncovered the unique functions of this complex. They demonstrated that this complex regulates the phosphorylation of many proteins involved in synapse structure and organization.
High-resolution imaging of the mutant mice brains revealed abnormal synapse organization, and further study of their signaling properties showed an increase in inactive synapses with defects in signal transmission. Observing the behavior of the mutant mice, the scientists saw that they exhibited elevated levels of anxiety, especially enhanced avoidance in unfamiliar conditions, and impaired social behaviors.
Reference: “The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation” by Husam Khaled, Zahra Ghasemi, Mai Inagaki, Kyle Patel, Yusuke Naito, Benjamin Feller, Nayoung Yi, Farin B Bourojeni, Alfred Kihoon Lee, Nicolas Chofflet, Artur Kania, Hidetaka Kosako, Masanori Tachikawa, Steven Connor and Hideto Takahashi, 27 September 2024, The EMBO Journal.
DOI: 10.1038/s44318-024-00252-9
Funding was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research grants, the Fonds de la recherche du Québec research scholars (FRQS) and the U.S. National Institutes of Health. Husam Khaled was a recipient of an FRQS Doctoral Scholarship and the IRCM Emmanuel-Triassi Doctoral Scholarship for this study.
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