Researchers at the University of Arizona have developed novel synapse manipulation tools, so called synapse surgery tools, using the endogenous synapse pruning system. Complement proteins tagging system for target synapses are effective in eliminating specific synapses relevant to neuronal functions and diseases. To accomplish this, the technology is designed with a cell-type-and circuit-specific complement tagging system using viral vectors in conjunction with transient activation protocols of glial cells in target areas using AAV vectors. The synapse removal tools are demonstrated at various levels of model systems including a neuropsychiatric disease model, to delineate circuit-specific pathophysiological mechanisms. An AAV vector has been developed (AAV-DIO-C3dg-Shisa6-HA) which delivers a complement C3 fragment to target excitatory synapses to be removed by activated microglial cells. Based on the initial tool, various genetic tools were designed to remove circuit specific synapses.
Many brain mapping projects are currently ongoing to reveal the connectivity of neurons in the brain. Synapses are the basic unit of information processing between neurons. Each neuron connects to others via 1,000 synapses on average, and mis-wiring or loss of connection via the synapses is the underlying cause of many neurological diseases. To test functional relevance of the discovery, optogenetic and pharmacogenetic tools have been widely used to control neural activities in circuit-specific manners. Although these tools can temporally control specific neural activities, they cannot physically modify the neural connections. Currently, the physical control of specific synapses in live animals is limitedly applicable while optical imaging, which has limitations such as low-throughput, technical complexity, and procedural invasiveness.
The synapse ablation tools allow remodeling of specific neural circuits at the level of synapses. The successful development of the synapse surgery tools in patents will allow the address of fundamental mechanisms of neuronal functions and related diseases and contribute to a wide range of neuroscience fields. Therefore, diagnosis of specific neuronal circuits that are causes of neurological diseases and the deployment of synapse surgery to offer therapeutic solution to permanently remove malfunctioning neural connections to restore neuronal circuits and relieve the symptoms is possible.
- Treatment of neurological diseases and disorders
- More effective
- Relieve symptoms
- Restore neuronal circuits
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