Use dependent regulation of the coupling distance between Ca2+ channels and release sensor as a mechanism of long-term plasticity

• Applicant: Professor Dr. Hartmut Schmidt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459058603

Information processing in the central nervous system relies on rapid chemical synaptic transmission and its modulation via synaptic plasticity. Upon action potential - mediated depolarization of a presynaptic terminal voltage-gated Ca2+ channels open and the inflowing Ca2+ triggers the fusion of transmitter-filled synaptic vesicles (SVs) at the synaptic active zone by binding to vesicular release sensor proteins. Ca2+ builds a steep, short-lived concentration gradient around the mouth of an open channel that rapidly diminishes with increasing distance from the channel. This makes the spatial coupling distances between channels and release sensors a key parameter of the efficacy of synaptic transmission. Two principle coupling configurations have been distinguished to date: tight nanodomain coupling and loose microdomain coupling. Tight coupling favors high synaptic efficacy, in particular high probability of release of SVs, while loose coupling is thought to provide more options for regulation. How the coupling distance itself is regulated is not well understood at present. At investigated synapses a developmental switch from loose microdomain to tight nanodomain coupling has been described that significantly altered synaptic efficacy. Synaptic efficacy is further regulated by presynaptic long-term plasticity, again in an age-dependent manner. Synapses in young cortex are biased towards long-term potentiation (LTP), while at mature synapses both, LTP and long-term depression (LTD) are induced according to classical plasticity rules. The relationships between active zone topographies and long-term plasticity are largely unclear at present. In this proposal, the following hypotheses are addressed: Young synapses are biased towards LTP because they have loose microdomain coupling and a tightening of the coupling distance is induced preferentially, independent of the details of the plasticity protocol. Mature synapses operate with tight nanodomain coupling and LTD increases the coupling distance. LTP may further tighten coupling at mature synapses but most likely involves further mechanisms, in particular recruitment of additional release sites. The project relates age-dependent differences in active zone topography to age-dependent differences in long-term plasticity, hence, establishing how processes and rearrangements at the active zone and long-term plasticity mutually influence each other. Since release and plasticity are at the core of neuronal information processing and cortical map construction, the project addresses a major gap in our understanding of synapse maturation and coding in the brain.

• DFG Programme: Research Grants