Periodic Reporting for period 4 - PreSynPlast (Molecular mechanisms of presynaptic plasticity)
Reporting period: 2025-03-01 to 2025-08-31
We aim to better understand the mechanisms of learning and memory. From newborn to elderly, learning and memorizing is essential for our lives. Impairments in learning and memory have immense implications for the society.
An important mechanism of learning and memory is synaptic plasticity. During synaptic plasticity the neurotransmitter release of the presynaptic cell and the response to the neurotransmitter of the postsynaptic cell can be altered. The presynaptic mechanisms of synaptic plasticity remain poorly understood. To investigate the presynaptic mechanisms we develop techniques that allowed to measure the function of the presynaptic nerve terminal more directly. We use special glass pipettes and position the tip of the pipette onto the nerve terminals to measure its function. In addition, we use super-resolution microscopic, genetic, and computational techniques to analyze the structural and functional changes in the presynaptic terminals.
An important mechanism of learning and memory is synaptic plasticity. During synaptic plasticity the neurotransmitter release of the presynaptic cell and the response to the neurotransmitter of the postsynaptic cell can be altered. The presynaptic mechanisms of synaptic plasticity remain poorly understood. To investigate the presynaptic mechanisms we develop techniques that allowed to measure the function of the presynaptic nerve terminal more directly. We use special glass pipettes and position the tip of the pipette onto the nerve terminals to measure its function. In addition, we use super-resolution microscopic, genetic, and computational techniques to analyze the structural and functional changes in the presynaptic terminals.
We established direct patch-clamp recordings from small conventional nerve terminals of neurons. We uncovered several mechanisms of presynaptic function such as the calcium-sensitivity of vesicle fusion, differences in plasticity of excitatory and inhibitory nerve terminals, and ectopic action potential initiation in axons of dopaminergic neurons. Our data show that a subset of synaptic vesicle, which is slowly recovering, is specifically increased during long term synaptic plasticity. To relate our findings in mice to humans, we studied the function of presynaptic terminals of human stem cell-derived neurons. We found similarities in the presynaptic function of mice and human neurons.
In addition, we studied the metabolic function of presynaptic terminals and found that the presynaptic ATP concentration decreases during physiological activity. We are now studying the metabolic constrains of long-term potentiation. Finally, we found that ketamine, which has rapid anti-depressant effects, profoundly potentiates glutamate release at a central presynaptic terminal. These findings will open new avenues for rapid antidepressant therapy.
In addition, we studied the metabolic function of presynaptic terminals and found that the presynaptic ATP concentration decreases during physiological activity. We are now studying the metabolic constrains of long-term potentiation. Finally, we found that ketamine, which has rapid anti-depressant effects, profoundly potentiates glutamate release at a central presynaptic terminal. These findings will open new avenues for rapid antidepressant therapy.
The established technique allows to analyze presynaptic function of small conventional boutons with unprecedented temporal resolution. We revealed mechanisms of presynaptic function such as the calcium-sensitivity of vesicle fusion, differences in plasticity of excitatory and inhibitory nerve terminals, ectopic action potential initiation in axons of dopaminergic neurons, a decrease in the presynaptic ATP concentration during activity, and a direct potentiation of glutamate release by ketamine. Our results provide a better understanding of the function and plasticity of presynaptic terminals. Ultimately, our work aims to reveal molecular pathways and metabolic constrains of presynaptic plasticity that are relevant in health and disease.