Neuronal communication is a complex process; synapses must be formed, neurotransmitter has to be released at precise time points and it has to be “sensed” by the receiving end of a synapse with an equal accuracy. In this highly coordinated ballet of proteins any change may result in disharmony and eventually in pathology. Therefore, any new addition during the course of evolution must be fulfilling a specific purpose. A relatively new protein in the evolutionarily highly-conserved presynaptic apparatus, since it is vertebrate specific, is Mover. It is attached to synaptic vesicles and interacts with Calmodulin and Bassoon, another vertebrate-specific active zone protein. Mover’s expression levels vary throughout the brain, suggesting a modulatory function at the operation of the synapses. Here, I aimed to elucidate Mover’s role in synaptic transmission in the calyx of Held, a central glutamatergic synapse, using a Mover knockout (ko) mice. To this end, I recorded spontaneous and evoked excitatory postsynaptic currents (epscs) from brainstem slices using a whole-cell patch clamp configuration. In the ko evoked epscs were slightly smaller, and took longer to reach the same steady-state levels as the wild-type upon high frequency stimulation. Applying a blind-source separation technique termed non-negative tensor factorization allowed me to distinguish between different subpools of vesicles. This analysis gave rise to a model in which the absence of Mover reduces the release probability of a subpool of vesicles, termed “tight-state” vesicles –referring to the conformation of the snare complex and its associated proteins. Additionally, the size of this pool is significantly increased, indicating a compensatory mechanism. In contrast, the loose-state synaptic vesicles, the functional precursors of the tight-state ones, are unaffected by the absence of Mover. These findings suggest that Mover modulates the initial release probability, by specifically influencing the subpool of these tight-state vesicles.
Significance At active zones, ubiquitous proteins tether neurotransmitter-laden vesicles to specialized release sites, make them fusion-competent, and regulate their exocytotic fusion. Can specialized, synapse-specific proteins modulate this machinery? If so, which steps do they regulate? Here, we study mice lacking the presynaptic protein Mover. Mover is absent in some invertebrates and restricted to certain synapses in the rodent brain. Using electrophysiology and mathematical analysis of transmitter release kinetics at the calyx of Held, we find that Mover regulates a subset of fusion-competent synaptic vesicles: Mover selectively affects the vesicles most poised to be released during the initial stages of activity. Thus, by analogy, if ubiquitous proteins are light switches, Mover is a dimmer in transmitter release.
The hippocampal synapses display conspicuous ability for long-term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long-term potentiation (LTP) compared with their dorsal counterpart when activated with high-frequency stimulation. Here, we show that low frequency, 10 Hz stimulation induced LTP more reliably in dorsal than in ventral CA1 field. Blockade of alpha5 subunit-containing GABAA receptors eliminated the difference between dorsal and ventral hippocampus. We propose that α5GABAA receptor-mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus.
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