Link to Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11185757/
We are excited to announce a new publication from Dr. John Marshall at Brown University made possible by FAST funding. The project started in late September 2022, aiming to modulate synaptic function with two novel compounds, Syn3 and D-Syn3.
This research represents a possible small-molecule approach (Pillar 3 – Downstream Targets) to potentially treat the synaptic dysfunction observed in AS as a result of the loss of functional UBE3A in the brain.
Neurons communicate through specialized structures called synapses. These connections between neurons in the brain can change their strength and efficiency over time. This process is fundamental to how the brain adapts to new information and experiences and how long-lasting memories are formed. Synaptic function is impaired in Angelman syndrome and likely underlies the increased seizure propensity and many of the behavioral changes in individuals living with AS. One strategy to treat AS is to develop a drug that could act on the mechanisms involved in synaptic function and improve the ability of neurons to communicate in the AS brain. The latest paper, published by Dr. John Marshall, describes just such a strategy.
Marshall’s research focused on finding molecular changes in the neurons of the AS mouse model. One defect identified was in the TrkB receptor signaling pathway, a pathway long known to be involved in the processes of how synaptic connections are strengthened. TrkB receptors in the brain act like specialized "locks" on the surface of neurons that can only be opened by specific "keys" which in this case are specific chemical messengers. When these messengers bind to TrkB receptors, it triggers a series of signaling events that are necessary for typical neuronal function and underlying processes like memory formation. Instead of creating a small molecule that targets the “keys” of TrkB receptors, Marshall used a small protein called SYN3 (synapsin-3) that targeted where the receptors anchor in the neuron, essentially making them accumulate at the synapse where they can have a greater effect!
These studies nicely show that targeting the anchoring of TrkB receptors to the synapse in a mouse model of AS can have multiple beneficial effects:
Recovery of Long-Term Potentiation (LTP): LTP is a cellular mechanism associated with memory formation and learning. By enhancing the anchoring of TrkB receptors to the synapse, Marshall demonstrated the restoration of LTP in the hippocampus of AS mice. This suggests an improvement in the brain's ability to strengthen connections between neurons, which is crucial for cognitive processes and is known to be altered in AS.
Rescue of Motor Coordination Defects: AS mice typically exhibit motor coordination deficits, which can be assessed using tasks like the accelerating rotorod. Targeting TrkB anchoring led to a rescue of these motor coordination impairments, indicating an improvement in motor function and motor memory.
Increased learning and memory: Treated AS mice show an increased ability to perform a novel object recognition test. Novel object recognition is a cognitive task used in research to study how animals perceive and remember new objects.
Improvement in Seizure Threshold and Hyperexcitability: Angelman syndrome is associated with increased susceptibility to seizures and hyperexcitability of neurons. Enhancing TrkB receptor anchoring significantly improved seizure threshold and reduced hyperexcitability in treated AS mice. This suggests that TrkB receptors have the potential for stabilizing neural activity and reducing the propensity and occurrence of seizures.
Overall, these findings highlight the therapeutic potential of manipulating TrkB receptor colocalization within the neuron for the treatment of Angelman syndrome. By targeting this specific aspect of TrkB signaling, Marshall and his team were able to overcome the effects of Ube3a deficiency without replacing the maternal gene (Pillar 1) or activating the paternal gene (Pillar 2).