Topic: gephyrin

During early stages of Alzheimer’s disease (AD) gradual accumulation and aggregation of Aβ oligomers (AβO) occurs prior to cognitive decline. This preclinical stage of AD is further characterized by synaptic dysfunction and network hyperexcitability. We recently discovered that 24-hour treatment of AβO​​​​​ to hippocampal slices impairs release at GABAergic synapses, most prominently at dendritic inhibitory synapses. This suggests that inhibitory synapses are particularly vulnerable to AβO toxicity.We currently use advanced imaging approaches in vitro to further investigate the mechanisms that

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) are responsible for a severe neurodevelopmental disorder, namely CDKL5 deficiency disorder (CDD), characterized by early-onset epileptic encephalopathy, intellectual disability, and intractable seizures. So far, the role of CDKL5 in excitatory synapses has been widely explored; conversely, more has still to be investigated regarding its influence on the inhibitory compartment. Our recent data showed that CDKL5 loss impacts the number of synaptic GABAARs, which may be explained by its interaction with the postsynaptic scaffolding comp

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders characterized by impairments in social behavior and communication. Traditional research on the biology of ASDs has focused on the central nervous system (CNS), aiming to identify brain regions, molecular mechanisms, and genetic mutations associated with ASDs. However, an increasingly holistic approach to ASDs demonstrated that there is comorbidity with immune and gastrointestinal (GI) dysfunctions. It is now accepted that there is a bidirectional communication between the gut and the brain, with the microbiota play

The dorsal dentate gyrus (dDG) plays a pivotal role in stress vulnerability and resilience. dDG granule cells interact with various interneuron subtypes, forming a complex local circuit essential for stress processing. Studies have shown differential activity in specific interneuron subtypes in response to stress, impacting coping mechanisms.This study examines the impact of two distinct categories of DG interneurons, chandelier and basket cells, on coping behavior. Ephrin A7 (EphA7) stabilizes synaptic terminals in basket cells, while Neurofascin (NF) facilitates axo-axonic synapse formation

Although excitatory cells comprise the bulk of hippocampal neurons, roughly 20 percent of the neuronal population is inhibitory. While an increasing interest in inhibitory signaling has led to the discovery of its importance for controlling episodic memory encoding and consolidation, its contribution to the function of individual engram neurons is largely unknown. In this project, we study GABAergic inhibitory synaptic plasticity in hippocampal engram neurons and its function in memory precision. We employ the Fos-TRAP2 system to label and manipulate contextual fear memory engrams in mice. We

The nanoscale arrangement of chemical synapses is thought to be critical for establishing synapse strength but whether this arrangement is sensitive to changes in in vivo activity is not known. Pyramidal neurons in the cortex receive a multitude of excitatory and inhibitory inputs that determine the generation of the action potential (AP) at the axon initial segment (AIS). Chandelier cells (ChCs), a GABAergic interneuron subtype, targets the AIS of pyramidal neurons through axo-axonic synapses and is therefore thought to strongly modulate neuronal output. We used super-resolution microscopy (S

Immunoglobulin superfamily member 9b (IgSF9b) is a cell adhesion protein that has been linked to the etiology of several psychiatric disorders, including bipolar disorder and schizophrenia. Based on previous studies in neuronal cultures, IgSF9b was proposed to specifically regulate the structure and function of GABAergic synapses in the brain through an indirect interaction with the synaptic adhesion protein Neuroligin-2. To date, however, very little is known about the expression pattern of IgSF9b in the intact brain, and the synaptic localization of IgSF9b in different brain regions has neve

The loss of a sensory input leads to reorganization of neuronal networks in remaining sensory cortices, which results in functional improvements. This shows remarkable adaptability of the mammalian brain. It remains elusive whether a traumatic brain injury (TBI) in a sensory cortex results in similar functional reorganization in spared sensory networks. We herein investigated global alterations in neuronal activity maps in the mouse brain subjected to a TBI in the visual cortex and delved into the underlying cellular mechanisms. Our data shows substantial differences in brain activity maps 2-3

Disrupted balance between excitatory and inhibitory neuronal activity is considered a main driver of AD pathogenesis contributing to cognitive deficits. We studied the protein expression of GABAA- and glycine receptor subunits as well as the protein level and phosphorylation of the inhibitory receptor anchoring protein gephyrin in a mouse model of AD and how treatment with artemisinins modulates these features. In hippocampal subregions of 12-months-old double transgenic mice which co-express the Swedish mutated form of the human APP (APPswe) and at L166P mutated human presenilin 1 (PS1) genes

Reactive oxygen species (ROS) play a central role in enhancing inhibitory signal transmission, thus extending their role beyond oxidative stress in disease and aging. However, the underlying molecular mechanisms mediating these functions have remained elusive. At inhibitory synapses, the scaffolding protein gephyrin clusters glycine and GABA type A receptors. Since gephyrin harbors multiple surface-exposed cysteines, we investigated the regulatory influence of ROS on gephyrin. We show that H2O2-induced oxidation of gephyrin cysteines triggered reversible, synaptic multimerization through disul

Glyphosate (Gly)-based herbicides (GBH), which are widely used worldwide, work by inhibiting the enzyme enolpyruvylshikimate-3-phosphate synthase, in the shikimate pathway, which functions in plants but not animals. Long-term exposure to GBH can cause toxic effects to the nervous system by affecting neurotransmitter expression, oxidative stress, anxiety, learning and memory impairments. Though Gly safety studies are still ongoing, little is known about the mechanistic processes underlying Gly neurotoxicity. Remarkably, few studies examined how the acceptable daily intake (ADI) dosage affects n

Synapses are established and maintained by adhesion molecules, which include post-synaptic neuroligins (NLGNs). In the absence of highly specific antibodies, the sub-cellular distribution and synaptic function of NLGNs have been extensively manipulated using knock-out, over-expression or rescues approaches, leading to controversial results. In this context, we generated a new transgenic knock-in mouse strain in which endogenous NLGN1 has been N-terminally tagged with a biotin acceptor peptide (bAP) by gene editing using the CRISPR-Cas-9 strategy. Native NLGN1 can be enzymatically biotinylated