Research groupJunior group

Noa Lipstein

Synapse Biology

portrait Noa Lipstein

The Synapse Biology group studies the process of information transfer between neurons in the brain. We aim to identify cell biological processes that shape synaptic function, and explore the relationship between the properties of the synapse and its molecular composition. Our work provides insight into the function of the brain in physiology and in disease.


Synapse Biology

The Synapse Biology group focuses on elucidating the contribution of synaptic proteins to neuronal function and plasticity, and on deciphering synaptic disease mechanisms in brain disorders. We combine genetic manipulations in mouse models with electrophysiological and cell type-specific biochemical tools to study the molecular composition and organization of synapses, with the aim of understanding how these parameters define synaptic function and dysfunction.

 

 

Research

Synapses mediate information transfer in the nervous system. They display remarkable functional diversity and are highly plastic throughout lifetime, during behaviour, and in disease. Both the diversity and the plasticity of synaptic function are critical for encoding complex information within neuronal networks, and are therefore essential for all brain functions. Failure of synaptic function, on the other hand, can lead to imbalance in the network and is identified as a major etiological cause in multiple forms of brain disorders, including in neurodevelopmental (e.g. autism spectrum disorders), neuropsychiatric (e.g. schizophrenia) and neurodegenerative conditions (e.g. Alzheimer‘s disease). In face of the continuously changing nature of synaptic function, a major challenge remains to understand how synaptic function is encoded by its molecular composition.

Diversity, Plasticity, and Dysfunction

Our group focuses on understanding the molecular and cell biological processes that shape synaptic function in health and disease. In particular, we are interested in understanding how functional synapse diversity is encoded by its molecular composition, and how this diversity shapes the expression of brain disorders. We use unique mouse genetics tools, electrophysiology, imaging, and -omics tools to draw a link between the functional state and the molecular state of the synapse. Our projects are centered around three key elements that define synapse function: Diversity, Plasticity, and Dysfunction.

Synaptic diversity

The complex and dynamic nature of the nervous system requires exquisite cellular specialization. A large cellular diversity is a unique feature of the brain, distinguishing it from other organs, and making it harder to decipher its function. A large fraction of this diversity is expressed at synapses: the estimated 1015 synapses in the human brain can be classified into multiple subtypes based on their morphology, electrical properties, and, most importantly, their functional output.

What defines synapse identity? We follow the hypothesis that synapse identity can be defined by a unique and specific combination of proteins that are organized spatially according to pre-defined transcriptional and translational templates. Understanding how the synaptic proteome is composed and organized will promote the discovery of novel mechanism of neurotransmission, disease mechanisms in brain disorders, and allow to predict functionality in synapses that are experimentally inaccessible.

Synaptic plasticity

Synapses are plastic - their strength adapts according to dynamic changes in the level or in the type of stimulation. Synaptic plasticity occurs, for example, during periods of increased/decreased neuronal activity, in response to particular stimuli, or during behavior, and it serves as a mechanism for short- or long-term storage of experience. Plasticity can sharply change synaptic function – and that change can last milliseconds, days, or throughout the lifetime of an organism. This plasticity is necessary for an array of functions, from the processing and integration of sensory information, to cognitive functions such as learning and memory.

Our group studies presynaptic mechanisms of plasticity formation. We previously identified Ca2+/calmodulin signaling (Lipstein et al., Neuron 2013) and Ca2+-phospholipids signaling (Lipstein et al., Neuron 2021) as major pathways that operate at the presynaptic active zone during periods of strong neuronal activity to enhance synaptic strength and the accuracy of information encoding. Current studies are focused on understanding how synaptic plasticity is changed by inborn synaptic disorders (see below), and how plasticity manifests in diverse synapse subtypes. We use slice electrophysiology, proteomics and structural methods to characterize changes that accompany short- and long-term synaptic plasticity events.

Disorder of the synaptic vesicle release site

Methodological advances in DNA sequencing for patient diagnosis have enabled the identification of hundreds of variations in synaptic genes, associated with a broad spectrum of brain conditions. The overwhelming number of disease-related variations presents multiple challenges: Are all variations pathogenic? How do they affect synapse function? Is each effect unique? Or can converging processes be identified?

Our lab is studying disorders of the presynaptic terminal. We aim to identify mechanisms by which pathogenic variations affect synaptic function, and to develop strategies for fast diagnosis of variant pathogenicity. We believe that the teamwork of clinicians, geneticist and wet-lab researchers is essential to enable translation of knowledge from bedside to bench and back.

Our primary focus lies on a brain condition associated with genetic variation in a central synaptic protein called UNC13A (also known as Munc13-1). UNC13A is a major component of the presynaptic terminal, mediating a molecular preparation step of synaptic vesicles called ‘priming’. Priming enables synaptic vesicles to fuse with the plasma membrane in response to a signal in the transmitting neuron, release their neurotransmitter content, and thereby convey the signal to the receiving neurons. Dysfunction of UNC13A is bound to cause a signaling imbalance along the neuronal network. Genetic variations in UNC13A that are associated with disease were only recently identified, and little is known about the clinical and genetic spectrum of this condition, as well as on the cell biological and molecular mechanisms that underlie it. We believe that identifying the mechanism by which variations affect synaptic function will contribute to the development of therapeutic approaches to alleviate accompanying symptoms.

To assess how the properties of synaptic transmission are modulated by disease-related protein variations, we conduct whole-cell voltage clamp electrophysiological recordings in single, autaptic neurons in culture (Lipstein et al., JCI 2017). This experimental model enables an exquisite and in-depth readout of cell-autonomous processes. We complement our functional studies with confocal- and super-resolution microscopy analyses and with mass-spectrometric approaches, aiming to achieve a comprehensive molecular-functional link of diseased synapses.

More about the condition and its underlying molecular mechanisms can be found under https://www.jci.org/articles/view/90259

We encourage clinicians, geneticist, and patient families to contact us for further details.


Group Members

 People

By PositionA-Z
  • Born in Israel, Noa completed her Bachelor studies at the Tel Aviv University. Inspired by a basic course in Biophysics, she decided to continue in a fast-route PhD program at the Tel Aviv University and join the lab of Dr. Uri Ashery, where she could practice electrophysiology in chromaffin cells. Her PhD project developed into a collaboration between the Ashery lab and the laboratory of Prof. Nils Brose at the Max Planck Institute of Experimental Medicine in Göttingen, combining mouse genetics and electrophysiology to study synaptic signaling pathways that control short-term synaptic plasticity (Lipstein et al., Neuron 2013). In her Postdoctoral studies, she continued these studies (Lipstein et al., Neuron 2021), and in addition characterized a new inborn brain disorder associated with variations in the UNC13A gene (Lipstein et al., JCI 2017). Since 2020 she leads the Junior Research Group ‘Synapse Biology’ at the FMP. Noa is a mother of one (2010) and is sharing her life between Berlin and Bielefeld, where her partner leads the Department of Biochemistry at the local University.

  • Kerstin completed her studies as a chemical-technical assistant at the Lise-Meitner-School in Berlin in 1995, and is a part of the LeibnizFMP team since 1996.

  • Sofia grew up in Hanover, Germany, where she received her B.Sc. degree in biology. During her studies in Göttingen towards a Master’s degree, she became interested in the molecular mechanisms of neurotransmitter release and joined the group of Dr. James Daniel at the Max Planck Institute of Experimental Medicine, and completed her M.Sc. degree in neurobiology in 2016 and doctoral degree in 2021. During her doctoral studies, she established a strategy for imaging of dopamine secretion events from ventral midbrain cultures using small optical dopamine sensors that are built from carbon nanotubes. At the FMP she will continue to explore the molecular composition of synapses.

  • During her Bachelor studies at the ‘Molecular Life Science’ program at the University of Utrecht, and one semester at the Philipps University in Marburg, Mareike developed a strong interest in molecular neuroscience. After completing her Bachelor thesis in the group of Dr. Ginny G. Farias, she was accepted to the Max Planck International Research School ‘Molecular Biology’ in Göttingen, where she completed her Master’s degree at the Department of Molecular Neurobiology in the Max Planck Institute of Experimental Medicine under the supervision of Dr. Noa Lipstein and Dr. Nils Brose. She started her PhD project at the Synapse Biology group in 2021.

  • During his studies towards a degree in German Philology, Sun discovered an interest in life sciences. He enrolled in the Bachelor program for Biochemistry and Molecular Medicine in the University Medical School Göttingen, and joined the Synapse Biology group at FMP the Berlin as a PhD student in 2021, exploring the fascinating world of Neurobiology.

Funding

NeuroCure cluster of Excellence: https://neurocure.de
SFB1286: https://www.sfb1286.de