Synapse formation

…transmission, axon guidance, synapse formation and neurodevelopmental disorders. Under the principal investigators, Project Scientists design, manage and conduct experiments, train students, lead lab projects, present at scientific meetings and write manuscripts and grant propo

Microglia-synapse interactions have been examined in a variety of contexts, in vitro and in vivo, which revealed an important role for microglia in synaptic pruning and loss. Nevertheless, it remains to be determined whether and how microglia are involved in the process of synapse formation under physiologic conditions. We hypothesize that microglia serve as a link between pre- and post-synapse by sensing neurotransmitter release at highly active pre-synaptic sites and actively modulate the formation of new dendritic spines.To examine this relationship, we target microglia-synapse communicatio

…CDH13 is involved in the regulation of synapse formation and maintenance, as well as serotonergic neuron development. Serotonergic neurons mainly originate from the raphe nuclei in the hindbrain. In mice, CDH13 is first detected roughly halfway through the embryonic development in the hindbrain. Studies suggest a role of CDH13 in the pathophysiology of neurodevelopmental disorders. After previously investigating the role of CDH13 during embryonic development, we now aimed for the analysis of

Synapse formation is critical for the wiring of neural circuits in the developing brain. The composition and function of synapses has predominantly been studied in rodent cells. Here we show a novel protocol to generate human iPSC-derived forebrain-like neurons that show rapid synaptic development. To achieve this, we use an astrocyte feeder layer attached to a complex mix of ECM-components. Neuronal stem cells (NCS) are plated on this layer for maturation into neurons. We use this protocol to provide an initial characterisation of Magi-family synaptic scaffolding proteins in human neurons. Bo

…are glial cells essential for synapse formation and refinement, but they also may react to inflammatory environment affecting neuronal network homeostasis. However, how an inflammatory episode occurring during fetal development influences astrocyte generation and phenotype remains largely unknown.In the brain, the innate immune molecule Pentraxin3 (PTX3) is produced by astrocytes and promotes the maturation of excitatory synapses. Its expression is induced by inflammatory stimu

Neurons communicate via synapses to allow normal brain functions such as cognition, memory formation, and learning. In these processes, synapses show plasticity and can be remodeled. Synapse formation is driven by synapse-organizing proteins that span the synaptic cleft to orchestrate the alignment of pre- and postsynaptic molecules. Recently, presynaptic α2δ proteins have been identified as crucial organizers of synapses by regulating axonal wiring, presynaptic differentiation, and postsynaptic receptor clustering. So far, α2δ proteins have been extensively studied as subunits of the voltage-

Perfluorinated compounds (PFCs) are organofluorine compounds containing carbon-fluorine and carbon-carbon bonds. They are used as water and oil repellants in clothes and pharmaceutical tablets, but have been found to cause neurotoxicity. However, it remains elusive whether PFCs affect neural survival or activity, or whether they alter different neuronal regulations in the brain. Additionally, there is a paucity of data on the regulatory mechanisms involved in PFCs-induced neural toxicity.In the current study, we report that PFOA or PFHpA differentially alter neural survival and activity in pri

Neurodevelopmental disorders (NDDs) pose a significant challenge to patients and their families, causing severe intellectual impairment, health complications and a diminished life expectancy. Yet, in approximately half of the affected individuals, the causal genetic variants remain elusive. Utilizing a comprehensive genetic screening strategy in a cohort of consanguineous families with multiple affected children, several gene variants associated with NDDs were identified. Among these, CLSTN1 emerged as a compelling candidate due to its high expression in the nervous system and high degree of c

Synapse formation, maintenance and function requires a continuous material supply from the neuronal soma, the site of protein production. Presynaptic material is suggested to traffic on highly specialised and diverse membranous organelles, the presynaptic precursor vesicles (reviewed in Petzoldt, Cells, 2023). Molecular mechanisms controlling their assembly and transport remain poorly understood. We could show that the small GTPase Rab2 is required in a Golgi-associated assembly sequence during early presynaptic precursor biogenesis (Götz … Sigrist, Petzoldt, JCB, 2021). Upon Rab2 depletion, b

The cerebellum critically contributes to motor, cognitive and emotional functions. Cerebellum-dependent motor learning is believed to be processed within the cerebellar cortex, and specifically via changes in synaptic plasticity of Purkinje cells (PCs), which are the main cortical output. However, whether and how motor learning can influence the actual connectivity of PCs is unknown. To address this question, we use a rabies virus (RABV)-based approach to map structural modifications of PC presynaptic inputs in young (3-month-old) and middle-aged mice (1-year-old). To promote motor skill learn

…neurotransmitter release and synapse formation b

While neuronal activity is important for synapse refinement and maintenance, its contribution to synapse formation and dendritic arborization remains unclear. Our previous work in dissociated hippocampal neurons identified a timeframe prior to the establishment of synapses during which spontaneous glutamate release facilitates the branching of dissociated hippocampal neurons by targeting NMDA receptors (NMDARs). We now demonstrate the role of NMDARs in synapse formation and dendritic maturation in hippocampal CA1 pyramidal neurons in cultured slices and in vivo. To test whether NMDARs guide sy

…a crucial role in the regulation of synapse formation and dendritic development of Purkinje cells. However, the precise mechanisms underlying these processes are not fully understood yet. In this project, our aim is to investi

…but intimately connected events of synapse formation, maturation, and the critical GABA shift, where GABAergic neurotransmission transitions from excitatory to inhibitory. The precise timing and intricate balance of excitatory and inhibitory signaling is crucial for establishing functional neural circuits, and when disrupted contribute to neurodevelopmental disorders (NDDs) like autism spectrum disorder (ASD) and epilepsy. Exploring human aspects of neuronal development and functioning face challenges due to limitation

Astrocytes and neurons collaboratively shape neural networks, influencing metabolism, synapse formation, and network dynamics. Dysfunctions in either cell type are implicated in diverse brain disorders. In order to gain insight into the transcriptional profile of hiPSC-derived astrocytes and neurons, we performed scRNA analysis and compared astrocytes and neurons before and after co-culture.Sequencing with Illumina Novaseq6000, preprocessing with 10x Genomics CellRanger. Custom R/Seurat pipeline for data analysis.NGN2 neurons were identified as excitatory. Within the astrocyte population we ob

…branching of their dendrites and the synapses they form with other neurons. During brain development, many dendrites grow simultaneously and become integrated into multiple networks. Extensive experimental data has demonstrated the role of synapse formation and neural activity on dendrite growth. Yet, computational models of dendrite growth mostly assume random branching, implement activity-independent growth cones or generate dendrite morphologies based on abstract mathematical constraints. While these approaches achieve highly

…context, readily form unspecific synapses. How does genetically encoded brain wiring deal with this apparent contradiction? Brain wiring is a developmental growth process that is not only characterized by precision, but also flexibility and robustness. As in any other growth process, cellular interactions are restricted in space and time. Correspondingly, molecular and cellular interactions are restricted to those that 'get to see' each other during deve

Almost everybody that has seen neurons under a microscope for the first time is fascinated by their beauty and their complex shape. Early on during development, however, there are hardly any signs of their future complexity, but the neurons look round and simple. How do neurons develop their sophisticated structure? How do they initially generate domains that later have distinct function within neuronal circuits, such as the axon? And, can a better understanding of the underlying developmental mechanisms help us in pathological conditions, such as a spinal cord injury, to induce axons to r

The synapse is the core component of the nervous system and synapse formation is the critical step in the assembly of neuronal circuits. The assembly and maturation of synapses requires the contribution of secreted and membrane-associated proteins, with neuronal activity playing crucial roles in regulating synaptic strength, neuronal membrane properties, and neural circuit refinement. The molecular mechanisms of synapse assembly and refinement have been so far largely examined on a gene-by-gene basis and with a perspective fully centered on neuronal cells. However, in the last years, the invol

Microglia are the immune cells of the brain, and play increasingly appreciated roles in synapse formation, brain plasticity, and cognition. A growing appreciation that the immune system involved in diseases like schizophrenia, epilepsy, and neurodegenerative diseases has led to renewed interest in how microglia regulate synaptic connectivity. Our group previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel regulator of microglial activation and function. I will discuss a mechanism by which microglia regulate synaptic plasticity and long-term memories by engulfing brai

Synapse formation during neuronal development is critical to establish neural circuits and a nervous system1. Every presynapse builds a core active zone structure where ion channels are clustered and synaptic vesicles are released2. While the composition of active zones is well characterized2,3, how active zone proteins assemble together and recruit synaptic release machinery during development is not clear. Here, we find core active zone scaffold proteins SYD-2/Liprin-α and ELKS-1 phase separate during an early stage of synapse development, and later mature into a solid structure. We directly