Inhibitory synapses

Inhibitory deficits and an excitation/inhibition(E/I) imbalance arising from loss of inhibitory synapses may predispose to subclinical-epileptiform-activity and contribute to the earliest stages of Alzheimer’s disease(AD), and progressively lead to macroscopic neuronal network dysfunction. The classical brain-criticality-hypothesis posits that neuronal-systems operate at a continuous, second-order phase-transition with E/I-balance serving as primary control parameter. However, we have recently found neuronal systems in vivo may also operate at a discontinuous, first-order phase-transition and

…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

The UBE3A gene codes for an E3 ubiquitin ligase and is critical to ensure a proper brain function. Indeed, perturbations of UBE3A dosage or function result in pathological phenotypes. Loss of UBE3A causes the Angelman Syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor delay and seizures, while increased UBE3A copy number or activity are strongly associated with Autism. Importantly, the molecular underpinnings of UBE3A-associated pathogenic mechanisms of neurodevelopmental disorders are still poorly understood. In this project, we study the effects of

…dynamics of these compartmentalized inhibitory synapses on PNs and their link to learning.To address these outstanding questions, we used longitudinal in viv

…relationship between excitatory and inhibitory inputs is established during the dynamic period of circuit wiring remains unexplored. Using multiple techniques, including in utero electroporation, electron microscopy and electrophysiology, we reveal a tight correlation in the distribution

…functional postsynaptic components of inhibitory synapses in the mammalian brain. They belong to a family of GABA-gated Cl/HCO3-permeable ion channels which are built as hetero-pentamers of subunits classified as α(1-6), β(1-3), γ(1-3), δ, ε, π, θ and ρ(1-3). How, where, and when the inhibitory synapses are formed is tightly regulated during early brain development and later synaptogenesis by genetic and environmental factors. Multiple proteins have been shown to participate in the initiation and func

How changes in synaptic connections underlie learning and memory is a central question in Neuroscience. Previous modeling efforts focused on biologically realistic learning rules and dynamics, but these rules usually produce bimodal weight distributions that are not aligned with experimentally observed lognormal distributions of synaptic weights. How biological learning rules preserve such unimodal distributions and at the same time retain information, i.e., learn, remains unknown. Here, we take a game-theoretical approach, asking whether learning is possible under the constraint of retaining

…to presynaptic inputs blocking inhibitory synapses. This disinhibits motoneurons causing dysregulated firing and tetanic contractions. Preferential actions on inhibitory synapses are usually explained by enrichment in the Vesicle-Associated Membrane Protein 2 isoform (VAMP2). VAMP1 and VAMP2 form part of the SNARE complex and are differentially distributed in different synapses. Nevertheless, the exact VAMP content inside synapses on mot

Maintaining the delicate balance between excitatory and inhibitory synaptic activity is crucial for proper brain function. The endosomal trafficking complex, retromer, plays a pivotal role in synaptic function by regulating the post-endocytic sorting of a variety of integral proteins at both excitatory and inhibitory synapses. As a result, SNX27/retromer is emerging as a potential mediator of excitatory/inhibitory crosstalk. In surface proteomic screens from primary cultured neurons, we have shown that a variety of subunits of γ-aminobutyric acid receptors (GABAARs) exhibit reduced surface exp

Acute brain slices represent a “workhorse” model for studying the central nervous system (CNS) from nanoscale events to complex circuits. While slice preparation inherently involves tissue damage, it is unclear how microglia, the main immune cells and damage sensors of the CNS react to this injury and shape neuronal activity ex vivo. To this end, we investigated microglial phenotypes and contribution to network organisation and functioning in acute brain slices. The comprehensive assesment of microglial states in acute brain slices demonstrated time-dependent microglial phenotype changes that

Different neurological diseases are characterized by an imbalance between excitatory and inhibitory synapses, including epilepsy or autism spectrum disorders (ASD). One of many genes linked to these conditions is the scaffold protein neurobeachin (NBEA), which has been previously described as essential for receptor targeting to the plasma membrane. While its role at excitatory synapses has been studied extensively, NBEA function at inhibitory synapses is still barely understood. Here we report that NBEA is recruited to the GABAergic synapses in an activity-dependent manner and interacts with t

The formation of new inhibitory synapses is essential to counterbalance a strong excitatory activity and maintain dendritic coordination between excitation and inhibition. We recently demonstrated that the activation of excitatory spines is followed by the production of endocannabinoids in dendrites, which mediates the formation of new inhibitory boutons via axonal CB1 receptors. Bouton formation was found to depend on an increase of the second messenger cyclic adenosine monophosphate (cAMP) and the activation of the downstream protein kinase A (PKA). We ask whether other neuromodulators are a

…the physiological functions of APP at inhibitory synapses remain to be defined. We to study the role of APP at inhibitory synapses onto CA3 pyramidal cells (PCs) as well as on the overall inhibitory balance within the CA3 network. We combine slice electrophysio

…counterbalanced by the formation of inhibitory synapses during the maturation of neuronal circuits. Although this process relies on neuronal activity, different types of pyramidal cells likely respond to changes in activity through the expression of cell-specific genes. How

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

Microglia are keen responders in numerous neurodevelopmental and neurodegenerative conditions, including in Multiple Sclerosis (MS). While previous studies hinted about microglia involvement in synaptic elimination, their correlation with the appearance of cognitive deficits in MS remains unclear. Here, we focused on understanding the impact of microglia in MS synapse pruning in the cognitive-related region, the hippocampus, using postmortem tissue of MS patients. Hippocampal samples were obtained from the Netherlands Brain Bank, including non-demented control (NDC) and MS donors that were mat

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output and how neurons are integrated in the surrounding neuronal network. Accordingly, neurons with aberrant morphology have been associated with neurological disorders. Dysmorphic, enlarged neurons are, for example, a hallmark of focal epileptogenic lesions like focal cortical dysplasia (FCDIIb) and gangliogliomas (GG). However, the regulatory mechanisms governing the development of dendrites are insufficiently understood. The evolutionary conserv

Coordination between excitatory and inhibitory synapses (providing positive and negative signals respectively) is required to ensure proper information processing in the brain. Many brain disorders, especially neurodevelopental disorders, are rooted in a specific disturbance of this coordination. In my research group we use a combination of two-photon microscopy and electrophisiology to examine how inhibitory synapses are fromed and how this formation is coordinated with nearby excitatroy synapses.

…selective plasticity of thalamic and inhibitory synapses within primary sensory cortex.

…of activity across populations of synapses – the fundamental elements of signal transfer within all brain circuits. A guiding hypothesis is that the plasticity of neurotransmission plays a major part in controlling the input-output relation of sensory circuits, regulating the tuning and sensitivit

The remarkable cognitive abilities characterizing humans has been linked to unique patterns of connectivity characterizing the neocortex. Comparative studies have shown that human cortical pyramidal neurons (PN) receive a significant increase of synaptic inputs when compared to other mammals, including non-human primates and rodents, but how this may relate to changes in cortical connectivity and function remained largely unknown. We previously identified a human-specific gene duplication (HSGD), SRGAP2C, that, when induced in mouse cortical PNs drives human-specific features of synaptic devel