Neurotransmitter release at neuronal synapses in the brain

Simulations of the machinery that fuses membranes and releases neurotransmitters at synapses (middle and right). Image of cultured hippocampal neuron, courtesy of Clarissa Waites, Columbia University (left).

Cognition and coordinated motor activity rely on tightly controlled release of neurotransmitters (NTs) at synapses where neurons communicate in the brain. Neurotransmission involves action potentials that arrive at axon terminals and open voltage-gated calcium channels. We are mathematically modeling the multi-component NT release machinery that senses the elevated calcium and fuses NT-containing synaptic vesicles with the plasma membrane on sub-millisecond timescales, creating a fusion pore. A major goal is to unravel the mechanisms of membrane fusion, using highly coarse-grained computer simulation methods and analytical approaches that describe the core SNARE proteins and other components such as synaptotagmin. Equally important are the mechanisms of regulation of the fusion pore which releases NTs into the synaptic cleft to activate the post-synaptic neuron and complete the neurotransmission step. Regulation of these processes enables synaptic plasticity, the modification of synaptic strength over time which is central to information storage and processing by neural circuits. A major question is how these processes become altered in neurodegenerative disorders such as Alzheimer’s or neurodevelopmental disorders such as epilepsy.

© O'Shaughnessy Group 2018