Area-specific differences in cortical presynaptic coupling distances

• Applicant: Professor Dr. Hartmut Schmidt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518845403

Information processing in the brain relies on synaptic transmission and plasticity. An action potential opens calcium channels at the presynaptic active zone. Inflowing calcium triggers the fusion of synaptic vesicles by binding to a vesicular release sensor protein. Yet, the calcium concentration rapidly decreases with increasing distance from the channel. This makes the spatial coupling distance between channels and vesicles a key determinant of the fidelity and plasticity of synaptic transmission. Two principle coupling configurations have been distinguished to date: tight nanodomain coupling and loose microdomain coupling. In the mature brain, tight coupling was found at different excitatory synapses with high transmission fidelity, in particular synapses transmitting frequency-coded sensory information or recurrent excitation. At these synapses, tight coupling developed from loose coupling during postnatal maturation. Loose coupling, on the other hand, was found in the mature brain at a highly plastic excitatory synapse in the hippocampus. However, whether this constitutes a general rule is currently unclear. In particular, it is unclear whether coupling distances and topographies differ at the same principal types of synapses if they are engaged in different functions. The neo- or isocortex is a morphologically homogeneous brain region that covers highly diverse functions, ranging from early sensory processing and motor control up to higher order associations and cognitive functions. Notably, all of these different functions are performed by the same archetypes of neurons and synapses albeit in different areas of the neocortex. Here, the hypothesis is put forth that area-specific functional differences in the mature neocortex are associated with or even arise from differences in the functional presynaptic nanoarchitecture of the same principal types of synapses if they are located in different cortical areas. Specifically, I propose that synapses between the principal pyramidal neurons in layers 2/3 and 5 in cortical areas engaged in lower order processing (e.g. primary somatosensory cortex) operate with tight nanodomain coupling and that this tight coupling develops during postnatal maturation. On the other hand, I propose that the same principal types of synapses operate with loose microdomain coupling even in the mature cortex if they are located in areas engaged in higher order processing (e.g. prefrontal cortex). These differences in the synaptic nanotopographies will give rise to characteristic differences in transfer fidelity and plasticity. Preliminary data in the proposal supports this hypothesis. I propose that a comparison of the developmental dynamics of coupling distances between the same archetypes of synapses in specific neocortical areas and layers will yield important novel insights into the presynaptic structure – function relationships and may ultimately even allow for deducing a general rule for these relationships.

• DFG Programme: Research Grants