left à right: Dr Hideto Takahashi et Husam Khaled
New work by the team of Dr. Hideto Takahashi, Director of the Synapse Development and Plasticity Research Unit at the Montreal Clinical Research Institute (IRCM) uncovered unique roles for a protein complex in the structural organization and function of brain cell connectivity, as well as in specific cognitive behaviors. This work was recently published in the prestigious journal The EMBO Journal, in collaboration with Dr. Steven Connor’s team at York University and Dr. Masanori Tachikawa’s team at Tokushima University. Dr. Takahashi is also Associate Research Professor, Department of Medicine (accreditation for the Molecular biology and Neuroscience Programs) at Université de Montréal.
Mental illnesses, such as anxiety disorders, autism, and schizophrenia, are among the leading 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. Therefore, it is essential 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. Dr. Takahashi’s lab 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 by the first author Husam Khaled, a doctoral student at the Takahashi 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.
In Depth
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.
By generating mice with specific genetic mutations that disrupt the TrkC-PTPσ complex, Dr. 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. Indeed, high-resolution imaging of the mutant mice brains revealed abnormal synapse organization, and further studying their signaling properties showed an increase in inactive synapses with defects in signal transmission. While following the behavior of the mutant mice showed that they exhibit elevated levels of anxiety, especially enhanced avoidance in unfamiliar conditions, and impaired social behaviors.
Why it’s important
Although defects in synapse organization are linked to many neuropsychiatric conditions, the mechanisms responsible for this organization are poorly understood. This work uncovered new roles for the molecular complex TrkC-PTPσ in synapse organization and protein phosphorylation mechanisms. Given their association with several neuropsychiatric disorders, these findings also provide valuable therapeutic insights.
“This study has two important points,” explains Dr. Hideto Takahashi. “One is to uncover novel molecular mechanisms for brain cell communication, and 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 for these disorders.”
Link to article: https://www.embopress.org/doi/full/10.1038/s44318-024-00252-9
Acknowledgements This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canadian Institutes of Health Research grants (CIHR), Fonds de la Recherche du Québec Research Scholars (FRQS) and National Institutes of Health (NIH). Husam Khaled was a recipient of an FRQS Doctoral Scholarship and the IRCM Emmanuel-Triassi Doctoral Scholarship for this study.
