Developmental changes in Ca2+ influx release coupling at the active zone of excitatory cortical synapses

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Information processing in the central nervous system (CNS) relies on rapid chemical synaptic transmission, which is triggered by calcium influx through voltage gated calcium channels. The coupling distance between the calcium channels and the transmitter filled vesicles at the presynaptic active zone is a critical determinant of speed, reliability and energy efficacy of this process. A tight, so called nanodomain coupling, favors the fidelity of transmission, while a loose, so called microdomain coupling, is associated with less favorable transmission characteristics. Initially only synapses of the peripheral nervous system, one brain stem synapse, and inhibitory CNS synapses were found to operate at nanodomain coupling. Young excitatory hippocampal and cortical synapses on the other hand operated at loose, microdomain coupling, which led to the general assumption about microdomain coupling at excitatory cortical synapses. Recent results from our group challenged the generality of this view, showing that the adult excitatory parallel fiber to Purkinje cell synapse of the cerebellar cortex, probably the most abundant synapse in the brain, operates at nanodomain coupling. An intriguing difference between our experiments and the preceding experiments on coupling at glutamatergic synapses is the age of the experimental animals: While experiments from the other labs were performed on young synapses, we analyzed the coupling distance in more adult animals. In this proposal, the hypothesis is put forth that the coupling distance underlies a developmental tightening. Support for this idea comes from published data from the Calyx of Held brain stem synapse and preliminary observations presented in this application, which, however, require substantially deeper investigation. In order to arrive at a more general conclusion, it is intended to probe coupling at young and adult excitatory synapses of both, the cerebral and the cerebellar cortex. Specifically, coupling will be analyzed at synapses formed between neocortical layer 5 pyramidal neurons and cerebellar parallel fiber synapses formed between granule cells and Purkinje cells. Knowledge about the coupling distance and its regulation is critical for correctly interpreting the efficacy of transmitter release and mechanisms of synaptic plasticity. Since release and plasticity are at the core of neuronal information processing, this knowledge is of general interest for understanding synapse maturation and coding in the brain.