FWF-Wittgenstein-Preis
Project title: Synaptic communication in neuronal microcircuits
Project leader: JONAS Peter M.
We thank the reviewers for granting permission to publish their reviews.
GABA release from PV- and CCK-interneuron output synapses
Running title: Mechanisms of GABA release in hippocampal circuits
Project leader: JONAS Peter M.
Project Description
Inhibitory synapses releasing the transmitter gamma-aminobutyric acid (GABA) play a key role in several neuronal network functions. They control principal neuron activity by feedback and feedforward inhibition, contribute to the generation of network oscillations, and participate in higher-order computations such as pattern separation or pattern completion. Furthermore, GABAergic synapses play crucial roles in neurological and psychiatric disorders. The growing list includes schizophrenia, autism, and neurodegenerative diseases. GABAergic synapses formed by different types of interneurons differ substantially in their functional properties, but the mechanisms underlying functional diversity remain unknown.
In the present project, we propose to compare the properties of identified output synapses of parvalbumin (PV)- and cholecystokinin (CCK)-expressing interneurons, which differ in efficacy, synchrony, and dynamics of transmitter release. Specifically, we want to address three main questions: (A) What are the biophysical mechanisms underlying differential signaling at the output synapses of PV+ interneurons versus CCK+ interneurons? We will focus on the key parameters, such as number of release sites, source-sensor coupling distance, and vesicle pool size. (B) What is the molecular machinery of exocytosis at the different types of inhibitory synapse? In particular, we want to study the role of Rab3-interacting molecules (RIMs), central organizers of the active zone, and synaptotagmins, putative Ca2+ sensors of exocytosis. (C) What are the structural changes associated with GABA release at different types of inhibitory synapse? Using the “flash and freeze” functional electron microscopy approach, we will address structural correlates of synchronous and asynchronous release, clathrin-dependent and -independent endocytosis, and fusion of large, dense-core vesicles containing peptides including CCK.
To examine the functional, molecular, and structural mechanisms underlying synapse-specific properties, we will combine cutting-edge paired and multi-cell recording in acute mouse brain slices, analysis of synaptic transmission after genetic elimination of active zone proteins, and morphological analysis by “flash and freeze” functional electron microscopy.
Level of innovation: The results emerging from this project will provide key information about the mechanisms of inhibitory synaptic transmission in the mammalian brain. Furthermore, the new data will provide an important basis for incorporating inhibitory synapses into network models. Finally, the expected findings will help in the understanding of the pathomechanisms of neurological and psychiatric diseases, in which GABAergic synaptic transmission is often perturbed.
Project title: Synapses, Cell types, and microcircuits in the human brain
Running title: Synaptic networks of human brain
Project leader: JONAS Peter M.
Co-author: Prof. Dr. Karl Rössler
Project Description
The human brain is a biological system with remarkable complexity, computational power, and energy efficiency. It can generate simple reactions within milliseconds (e.g. reflex responses), integrate and process complex input signals over seconds (e.g. spatial navigation), and store information during the entire lifetime of a human being (e.g. learning and memory). A widely held assumption is that the functional properties of cells and circuits in humans are similar to those in lower species, but final proof for this assumption is lacking. On the other hand, it is often believed that certain properties of the human brain are unique, but how this uniqueness is achieved at the synaptic, cellular, and microcircuit level remains unclear.
The goal of the present project is to study synapses, cell types, and microcircuits in the human hippocampus. We want to focus on the dentate gyrus, a putative pattern separation circuit, and the hippocampal CA3 region, a putative pattern completion circuit and the largest autoassociative neuronal network in the brain. We plan to address three main questions: (A) What are the network properties of the human dentate gyrus? We will focus on the abundance of lateral inhibition, the properties of granule cell dendrites, and the potential contribution of newborn neurons. (B) What are the properties of the human mossy fiber pathway, which connects the dentate gyrus to the CA3 region? We plan to examine the electrical properties of human hippocampal mossy fiber terminals by subcellular recording, address whether they establish detonator synapses, and test whether they show similar forms of presynaptic plasticity in humans and rodents. (C) What are the network properties of the human CA3 region? We will study the rules of synaptic integration in CA3 cells by cable modeling, examine the active properties of CA3 cell dendrites by subcellular record-ing, and probe CA3–CA3 recurrent connectivity with multi-cell electrophysiology.
To address these questions, we will apply cutting-edge subcellular and multi-cell recording to acute human brain slices. Human tissue samples will be provided by the Neurosurgery Department of the Medical University of Vienna (MUW). We will focus on hippocampal tissue lacking structural alterations (“MRI negative”), allowing us to study the properties of the largely intact circuit.
Level of innovation: The results emerging from this project will lead to a unique data set. As very little is known about synapses, cells, and circuits in humans, the expected data will fill a major gap in our knowledge about the most complex organ of the human body. The findings will provide an answer to the long-standing question of whether the human hippocampus is simply a scaled version of its rodent counterpart, or whether specific properties of synapses, cells, and circuits contribute to its unique performance. In the long term, the results will also provide the basis for a better understanding of diseases of the human brain.
Cluster of Excellence – Excellent Brains
More info here.
Official Website here.