Elucidating the presynaptic roles of the α2δ family of proteins

Our brains work by sending information between billions of nerve cells, or neurons, through connections called synapses. At each synapse, one neuron releases chemicals (the sending neuron) that are picked up by another (the receiving neuron), allowing for the flow of information from one neuron to another. This process relies on many different molecules working together in a highly coordinated way. One group of molecules, called the α₂δ proteins (alpha-2-delta), helps control how calcium enters neurons, which is the essential step for triggering the release of these chemical messages. The α₂δ proteins are also targeted by common drugs used to treat conditions like epilepsy and chronic pain. However, it is unclear what α₂δ proteins do at the sending side of synapses. To find out, we created a special mouse model that lets us remove the three main α₂δ proteins only from the sending part of a synapse, without affecting the receiving side. We found that removing these proteins reduced the amount of calcium channels and another critical protein, Munc13, at the synapse, leading to less signal being sent, but there was no change in the shape or structure of the synapse. This suggests that α₂δ proteins are crucial for making sure the molecular machinery needed for sending signals is present in the right amount. Our findings help explain how these proteins support communication in the brain and could lead to better ways to treat neurological diseases by targeting them more precisely.