Volume 26, Issue 4

Research driven solely by curiosity and the desire to understand fundamental principles of brain function. The freedom to address important questions with bold, sometimes risky experiments. A platform for open scientific exchange and discussions at highest academic level to provide new impulses to the field. And a growing number of scientists who share the passion for neuroscience and who join forces to tackle some of the big mysteries that surround the brain. These visions together with the deep conviction that basic research is the fundament needed for any progress in applied science motivated Dr. Armin Schram to create the foundation that carries his name. They are also the ideals that the foundation still pursues, and to date, 26 research proposals designed by individual researchers or small teams have been, or are, supported in this spirit. Here, we introduce the reader to the individual scientists who were awarded grants by the Schram Foundation over the years, highlight some of the many discoveries made in the course of their studies and list some of the key publications that arose from this work.

Communication in the central nervous system is based on the transmission of electrical signals at specialized junctions between nerve cells termed synapses. During chemical neurotransmission, tiny membrane spheres called synaptic vesicles that are packed with neurotransmitters elicit a postsynaptic response by fusing with the presynaptic membrane and releasing their content into the synaptic cleft. Synaptic vesicle fusion is followed by the reuptake of the membrane by endocytosis and the local reformation of functional synaptic vesicles within the presynaptic compartment to sustain further rounds of neurotransmitter release. Here, we provide an overview of the clathrin-associated endocytic adaptor proteins that help to sort and recycle synaptic vesicles during presynaptic activity. These adaptors also serve additional functions in the turnover of defective or aged synaptic components and in the retrograde axonal transport of important signaling molecules by regulating the formation or transport of autophagosomes. Endocytic adaptors thus play multiple roles in the maintenance of synaptic function. Defects in their expression or function can lead to neurodegenerative and neurological diseases.

The synaptic vesicle (SV) cycle, a trafficking pathway by which SV fuses with the plasma membrane to release neurotransmitters at the neuronal synapse, resides at the heart of neurotransmission. SV fusion consumes vesicle membrane and proteins, whose availability is limited, and these components must be recycled quickly to prevent synaptic fatigue. Biochemical, genetic and physiological approaches over the past five decades have led to a discovery of a large directory of proteins and lipids central to the SV cycle and several models on how these constituents account for the synapse function. The complexity of the SV cycle is starting to be comprehended, which opens new perspectives for our understanding of neuronal physiology and provides mechanistic explanations for several neurological and neurodegenerative diseases. Here, selected classic and recent insights into the mechanisms of two key SV trafficking steps (exocytosis and endocytosis) are reviewed, as well as their links to selected brain pathologies.

In compact brains, circuits consisting of few neurons fulfill functions of entire brain systems in mammals. Thus, studying these small circuits can provide insights and guidelines also for the study of the human brain. We developed methods and approaches to use optogenetics in the nervous and neuromuscular system of the nematode Caenorhabditis elegans . These include single-cell expression and/or photoactivation of optogenetic tools, to control the function of individual neurons, and behavioral, electrophysiological or electron microscopic analyses of circuit function and synaptic transmission. We studied a number of circuits involved in locomotion, navigation and food searching; we addressed new genes in synaptic vesicle recycling, and we identified a novel pathway of neuromodulatory presynaptic plasticity. In our laboratory, support by the Schram foundation allowed me to explore new avenues of research especially during the early years of my career.

Over the last two decades, it has become clear that classical molecules that regulate neurodevelopment also play an important role in directly regulating the development of the vascular system and vice versa . The prototypical angiogenic ligand vascular endothelial growth factor (VEGF) is by now also regarded as a molecular regulator of different neurodevelopmental processes, such as neuronal progenitor proliferation, migration and differentiation, dendritic and axonal branching and synaptogenesis. The direct effect of other classical angiogenic factors, such as angiopoietins and its receptor Tie2, on neurodevelopmental processes remains less defined. Recent work from our group indicates that the angiopoietin-Tie2 pathway does not only regulate blood vessel formation and stabilization but also simultaneously affect neuronal dendritogenesis in a cell-autonomous manner. In this mini-review, we will integrate our findings within the current understanding of the neurovascular link and within the previous knowledge of the potential effects of angiopoietins in the neuronal context.

The hippocampus is decisive for the storage of conscious memories. Current theories suggest that experience-dependent modifications in excitation–inhibition balance enable a select group of neurons to form a new cell association during learning which represents the new memory trace. It was further proposed that particularly GABAergic-inhibitory interneurons have a large impact on population activity in neuronal networks by means of their inhibitory output synapses. They synchronize active principal cells at high frequencies, thereby supporting their binding to cell assemblies to jointly encode information. However, how cell associations emerge in space and time and how interneurons may contribute to this process is still largely unknown. We started to address this fundamental question in the dentate gyrus (DG) as the input gate of the hippocampus, which has an indispensable role in conscious memory formation. We used a combination of in vivo chronic two-photon imaging of population activity in the DG and the hippocampal areas CA1–3 of mice exposed to a virtual reality, in which they perform a goal-oriented spatial memory tasks, with high-density in vivo recordings and multiple whole-cell recordings in acute slice preparations, to determine how memory engrams emerge during learning. We further examine how GABAergic interneurons may contribute to this process. We believe that these lines of research will add to a better understanding on the mechanisms of memory formation in cortical networks.