By creating mice with genetic alterations that interfere with the brain’s TrkC-PTP protein complex, scientists have identified a crucial mechanism for brain cell communication.
Researchers at the Université de Montréal and the Montreal Clinical Research Institute (IRCM) have revealed distinct functions of a protein complex that is vital for the structural arrangement and operation of brain cell connections, as well as its impact on specific cognitive behaviors.
This research was conducted by a team led by Hideto Takahashi, who directs the IRCM’s research unit focused on synapse development and plasticity, along with collaborators Steven Connor from York University and Masanori Tachikawa from Tokushima University in Japan. Their findings are published in The EMBO Journal.
While issues in synapse organization are linked to various neuropsychiatric disorders, the exact processes causing these disruptions remain largely unknown. The researchers believe their findings could offer important insights for future therapies.
Takahashi highlighted two primary objectives of this research:
“One is to uncover new molecular mechanisms involved in brain cell communication,” he explained. “The other is to create a novel animal model for anxiety disorders that exhibit panic disorder and agoraphobia-like behaviors, aiding us in developing innovative therapeutic approaches.”
Exploring the mechanisms
Mental health conditions such as anxiety disorders, autism, and schizophrenia rank among the most significant health challenges in Canada and across the globe. Despite their widespread occurrence, the development of effective medications and treatments for these conditions has been difficult, primarily due to the brain’s complexity. Consequently, researchers strive to elucidate the fundamental mechanisms that contribute to cognitive disorders to improve treatment methodologies.
Synapses are the connections formed between two neurons (brain cells) and are crucial for transmitting signals and ensuring proper brain function. Problems with excitatory synapses—responsible for initiating signals to target neurons—and their molecular components can lead to various mental health issues.
Takahashi’s team previously identified a new protein complex within synapses known as TrkC-PTPσ, exclusive to excitatory synapses. The genes that encode TrkC (NTRK3) and PTPσ (PTPRS) have been linked to anxiety disorders and autism, respectively. However, the precise ways in which this complex influences synapse development and cognitive functioning are still unclear.
The new study, led by first author Husam Khaled, a doctoral student in Takahashi’s lab, demonstrated that the TrkC-PTPσ complex plays a role in regulating the structural and functional development of excitatory synapses by managing the phosphorylation—a type of biochemical modification—of various synaptic proteins. When this complex is disrupted, specific behavioral issues arise in mice.
Fundamental components of the brain
Neurons are the essential units of the brain and nervous system, responsible for transmitting and receiving signals that regulate brain and body functions. Adjacent neurons engage with each other through synapses, which serve as pathways for signal exchanges.
Such communication is vital for proper brain activities, including learning, memory, and cognition. Any flaws in synapses or their components can interfere with neuron communication, potentially leading to a range of brain disorders.
By engineering mice with particular genetic mutations that disrupt the TrkC-PTPσ complex, Takahashi’s group discovered the specific roles of this complex. They found that it governs the phosphorylation of several proteins that contribute to synaptic structure and organization.
High-resolution imaging of the brains of these mutant mice revealed irregular synapse organization, and further analysis of their signaling functions indicated an increase in inactive synapses, accompanied by signaling deficits. Behavioral observations of the mutant mice showed elevated anxiety levels, particularly a heightened tendency to avoid unfamiliar situations, along with compromised social interactions.
