Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - GIANTSYN (Biophysics and circuit function of a giant cortical glutamatergic synapse)

Teaser

The highly ambitious goal of the project GIANTSYN is to understand the hippocampal mossy fiber synapse, a key synapse in the hippocampal microcircuit, at all levels of complexity. At the subcellular level, we want to unravel the mechanisms of transmission and plasticity in the...

Summary

The highly ambitious goal of the project GIANTSYN is to understand the hippocampal mossy fiber synapse, a key synapse in the hippocampal microcircuit, at all levels of complexity. At the subcellular level, we want to unravel the mechanisms of transmission and plasticity in the same biophysical depth as previously achieved at the neuromuscular junction or the calyx of Held. At the circuit level, we want to understand the connectivity of this synapse and the contribution to learning and memory. Thus, by the end of this project the hippocampal mossy fiber synapse could become the first synapse in the history of neuroscience where we reach complete insight into both synaptic biophysics and contribution to higher network computations. In the long run, the results may open new perspectives for the diagnosis and treatment of brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.

Work performed

In the first reporting period, we already made very good progress towards reaching these highly ambitious goals. First, using paired recordings between mossy fiber terminals and postsynaptic CA3 pyramidal cells, we found that hippocampal mossy fiber synapses were not only conditional detonators, but also plasticity-dependent detonators, identifying a critical role of plasticity in synaptic computations (Vyleta et al., 2016, eLife; Borges-Merjane et al., in preparation). Second, using paired recordings we found that posttetanic potentiation did not primarily increase release probability, as previously assumed, but rather augmented the size of the readily releasable pool, measured by analysis of cumulative release during trains of 10 action potentials (Vandael et al., in preparation). Third, using the novel flash-and-freeze technique, we were able to show that optogenetic stimulation of hippocampal mossy fibers depleted the pool of docked vesicles in active zones of hippocampal mossy fiber synapses. Following depletion, the pool not only recovered back to the control value, but rather became larger in comparison to control conditions (Borges-Merjane et al., in preparation). This pool overfilling may contribute to posttetanic potentiation observed in our electrophysiological paired recording experiments. Fourth, we extensively characterized the activity of granule cells in vivo in awake mice running on a linear treadmill. We discovered that granule cells fire action potentials only very sparsely, but if they fire, they often generate bursts or superbursts of activity. Intriguingly, we found that superbursts are sufficient to induce PTP at hippocampal mossy fiber synapses (Zhang et al, in preparation). Finally, we established a large-scale model of the dentate gyrus-CA3 network. We found that a winner-takes-all mechanism mediated by lateral inhibition in the dentate gyrus provides a highly efficient mechanism for pattern separation, and that pattern separation can be amplified by the subsequent mossy fiber-CA3 pyramidal neuron synapses (Espinoza et al., 2018, Nature Communications; Guzman et al., in preparation).

Final results

The project GIANTSYN addresses fundamental questions in the fields of synaptic transmission and circuit function. Given the rapid progress in the establishment of the new techniques, especially flash-and-freeze technology, we are optimistic that we can reach the major goals outlined in the original application. If the GIANTSYN project continues to be successful, it could provide a role model of how we are going to analyse the relation between structure and function in the brain and how we can close the huge gap between the cellular-synaptic level and circuit-behavioural level in the next decade.