Synaptic communication in neuronal microcircuits

One of the worlds leading neuroscientists, Peter Jonas is particularly renowned for his contributions to an understanding of synaptic transmission in neuronal micro-circuits. His main research interest being synaptic transmission, Peter Jonas investigates how synapses facilitate the communication between neurons. Given that the human brain has about 10 billion neurons and a thousand trillion synapse connections, understanding how these neuronal micro-circuits function represents one of the greatest challenges in the field of life science in the 21st century. Synapses in the brain fall into two categories: excitatory synapses releasing the neurotransmitter glutamate and inhibitory synapses releasing the neurotransmitter -amino-butyric acid (known as GABA for short). The group of Professor Jonas wants to quantitatively address the mechanisms of synaptic signalling at these highly specialized synaptic sites in the brain. To achieve this, they will use multiple-cell recording, subcellular patch-clamp techniques, Ca2+ imaging, and modelling. One focus area is the investigation of inhibitory GABAergic interneurons. These inhibitory cells play a vital role in information processing in the hippocampus and neocortex. Within milliseconds, these cells convert excitatory into inhibitory signals in order to protect the brain against excessive discharges, as found in epileptic fits, for instance. The researcher seeks to arrive at a quantitative understanding of signalling at the nano-physiological level in order to develop a complete mathematical model of these interneurons. Among other achievements, his research has revealed a hitherto unknown subcellular mechanism serving to transmit action potentials quickly and reliably though a controlled increase in the sodium channels and sodium conductivity of the axons. Another main research area is signalling at the so-called hippocampal mossy fibre synapses. This type of synapse is of central significance for higher brain functions since it is located in a circuit that is relevant for learning and memory. Many network functions of this synapse are still largely unknown. Jonas studies the biophysical properties of this synapse, but also its function in the neuronal network. For his investigations he employs ultramodern techniques used in electro-physiology, imaging and optogenetics, but also structural biology techniques. The mossy fibre synapse could thus become the first synapse in the history of neuroscience of which scientists have a complete understanding with an eye to the relationship between synaptic biophysics and higher network functions. With funding from the Wittgenstein Award, Peter Jonas will be able to address a particularly exciting question in neuroscience: the interrelation between structure and function in synaptic signalling. His goal is to detect the structural changes during synaptic transmission by combining optical stimulation with analysis by electron microscopy. These studies will provide a precise idea of the molecular, structural and functional levels of signalling at excitatory and inhibitory synapses. Peter Jonas intends to find answers to one of the fundamental questions in neuroscience by using an interdisciplinary approach working partly with other research groups at IST Austria: the physical appearance of structural correlates of synaptic signalling and synaptic plasticity.

Understanding the function of the brain is a major challenge in the 21st century. The human brain is comprised of ~100 billion neurons, which communicate with each other through ~1 quadrillion of contact sites, termed synapses. Although our knowledge about the function of this extremely complex system has substantially increased, several fundamental questions remain unresolved. Funded by the Wittgenstein award, we have focused on two of these questions. First, what is the relation between functional properties and structural changes at synapses? This is a key question, because structural changes at synapses may be related to information stored in neuronal networks ("engrams"). Second, how do specific synaptic properties generate higher-order network computations? This is an important question, not only for elucidating brain function, but also for understanding brain dysfunction, for example in neuropsychiatric diseases. We have tackled these questions using a combination of cutting-edge electrophysiology, structural-morphological analysis, and computational modeling. We have identified structural correlates of several biophysical parameters of synaptic transmission, including number of transmitter release sites, coupling between presynaptic calcium channels and synaptic vesicles, and size of the vesicular pool. The results may help to define structural "engrams" as correlates of stored information. We have identified novel macroscopic and microscopic connectivity features in the hippocampus, a circuit that was thought to be fully understood for a long time. Our macroscopic connectivity analysis identified a previously unknown synaptic input from deep layers of the entorhinal cortex, suggesting parallel processing of information in the hippocampus. Our microscopic connectivity analysis revealed that connectivity in the CA3 network is sparser than previously thought, but is enriched in nonrandom connectivity motifs. Using in vitro recordings, in vivo measurements, and computational modeling, we succeeded to overcome the huge gap between the cellular-synaptic and the systems-behavioral level. Our combined experimental-theoretical approach has shed new light on the mechanisms of information processing by pattern separation, information storage by synaptic plasticity, and information retrieval by pattern completion in the hippocampal CA3 network. Finally, we have studied the properties of synapses in human hippocampal nervous tissue. Our results suggest that many synaptic properties are evolutionarily conserved from rodents to humans. However, our experiments also identify human-specific rules of synaptic connectivity, which may contribute to the uniqueness of the human brain. Taken together, the results enabled by funding from the Wittgenstein award substantially increased our knowledge about neurons, synapses, and circuits across species, providing new insights into the complex relations between synaptic structure, synaptic function, and higher-order computations in the brain.