Regulation of post-synaptic receptor recycling by synaptotagmin 3
Final Report Abstract
An important property of the brain is the ability to learn from experience by changing the strength of connections between neurons. These connections - termed synapses - are formed between a presynaptic neuron that releases neurotransmitter, and a post-synaptic neuron that takes up this neurotransmitter via receptors to transmit the signal. The trafficking of receptors to and from the surface of post-synaptic membranes regulates synaptic strength. High-frequency stimulation of connected neurons increases surface receptors at synapses and strengthens synaptic connections. This phenomenon underlies learning in the hippocampus, a memory center of the brain. Conversely, low-frequency stimulation removes receptors from post-synaptic membranes and weakens synaptic connections, and promotes forgetting. Although the ability to learn and remember is often regarded as the most important aspect of memory, forgetting is equally important. Without it, the relative importance of acquired memories in a changing environment is lost. In the most extreme case, deficits in forgetting can lead to post-traumatic stress disorder. We discovered that Synaptotagmin-3 (Syt3) – a member of a family of integral membrane proteins that senses calcium to regulate membrane recycling events – promotes forgetting by internalizing post-synaptic AMPA receptors to weaken synapses. We found that Syt3 localizes to post-synaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term weakening of synapses, and decay of long-term strengthening of synapses required calciumsensing by Syt3, and were abolished by removing Syt3. In spatial memory tasks mice lacking Syt3 learned normally, but lacked the ability to forget. Disrupting Syt3:GluA2 binding with an interfering peptide mimicked the lack of decay of synapse strength and lack of forgetting caused by removing Syt3, and this peptide had no effect when Syt3 was removed. Our findings provide evidence for a molecular mechanism whereby Syt3 internalizes AMPA receptors to weaken synaptic strength and promote forgetting.
Publications
- Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science 2019 Jan 4;363(6422)
Awasthi A, Ramachandran B, Ahmed S, Benito E, Shinoda Y, Nitzan N, Heukamp A, Rannio S, Martens H, Barth J, Burk K, Wang YT, Fischer A, Dean C
(See online at https://doi.org/10.1126/science.aav1483)
