Biology subjects

Kittel, R.

Publications and source records attributed to Kittel, R..

4 recordsLinked to original sources

bioRxiv2026

A Normative Model Reveals Functional Optimization of Synaptic Nano-Architecture

Super-resolution microscopy approaches have revealed that synaptic proteins are not randomly distributed within individual synapses. Rather, they form sub-synaptic clusters that may be coordinated between the synaptic compartments, thereby forming transsynaptic nanocolumns. However, the functional significance of this nano-architecture remains under debate. In particular, it is unclear whether the positions of synaptic proteins optimize a specific cost function. Here, we present a normative modeling framework that integrates synaptic nano-architecture imaged with STED and dSTORM microscopy with synaptic transmission recorded with electrophysiology at the Drosophila neuromuscular junction (NMJ). Model-based quantification showed that clusters of Unc13A, which likely demark presynaptic release sites, and postsynaptic glutamate receptors (GluRs) adopt aligned ring-like arrangements in individual synapses. We developed an analytical description of GluR activation relative to presynaptic release position, enabling to link super-resolution imaging data with recorded postsynaptic current amplitudes without relying on costly Markov chain Monte Carlo (MCMC) simulations. Our model predicts that glutamate released from a single vesicle spreads across the entire receptor population. Given this spread, the postsynaptic current amplitude is maximized when glutamate is released close to the active zone (AZ) center, in contradiction to the observed offset of Unc13A clusters. However, the observed relative positions of Unc13A and GluR clusters maximize the postsynaptic current amplitude and minimize the delay between vesicle release and receptor activation during multivesicular release. Hence, transsynaptically-aligned Unc13A-GluR rings optimize for multivesicular but not univesicular release. Given that multivesicular release is mainly observed during enhanced presynaptic release at the Drosophila NMJ, transsynaptic nano-architecture may be adapted to elevated presynaptic release states.

neuroscience↗

bioRxiv2025

Stabilized ion selectivity corrects activation drift in kalium channelrhodopsins

Effective optogenetic inhibition of neuronal activity requires tools that can reliably silence neurons across diverse conditions and cell types. Potassium-selective channelrhodopsins (KCRs) have emerged as promising alternatives to chloride-conducting channels for optogenetic inhibition of cellular excitability, but they exhibit dynamic ion selectivity shift under prolonged or intense illumination, causing activation. This inhibition to activation transition limits their utility for silencing circuits. Through behavioral and electrophysiological analyses in Drosophila, and C. elegans, we found that the C29D variant of KCR1 maintains the most stable potassium selectivity among tested variants. While other KCR variants showed excitation defects, KCR1-C29D consistently provided robust in vivo inhibition across cell types, illumination conditions, and species. Electrophysiological recordings revealed that while most KCRs show declining PK/PNa ratios during illumination, KCR1-C29D maintains stable ion selectivity, consistent with its robust silencing capability. This work resolves a key limitation of KCR optogenetics and shows that KCR1-C29D is a superior tool for reliable inhibition. Our findings offer valuable mechanistic and practical insights for the design of next generation optogenetic inhibitors.

neuroscience↗

bioRxiv2024

Neuropathic pain and distinct CASPR2 autoantibody IgG subclasses drive neuronal hyperexcitability

Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain, in some patients even as the only symptom. CASPR2 is an adhesion protein of the neurexin IV family and part of the voltage-gated potassium channel complex (VGKC) in neurons of dorsal root ganglia (DRG). The subsequent pathological mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass. Previous studies have neglected subclass-dependent effects. Here we investigated 49 subclassified patient serum samples positive for CASPR2 aAbs. To unravel underlying molecular mechanisms, we used a combination of super-resolution lattice structural illumination microscopy (SIM2) and functional readouts by calcium imaging and electrophysiological recordings. CASPR2-positive patient sera subclassified in IgG4 together with at least one other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain group. Patient subclassification shed further light on the pathological mechanisms of CASPR2 aAbs. A decrease of CASPR2 expression after long-term exposure to CASPR2 aAbs was only observed for the patient group without pain. Upon withdrawal of the CASPR2 aAbs, CASPR2 expression returned to normal level. Structural alterations were obtained by increased distances between CASPR2 and associated potassium channels along DRG axons using high-resolution lattice SIM2 microscopy but only following binding of CASPR2 aAbs from patients with pain. Similarly, CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all four CASPR2 aAbs subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs. Notably, a patient serum sample lacking IgG4 did not alter Kv channel function. Withdrawal of aAbs rescued Kv channel function to normal levels suggesting that the affected potassium channel function is rather due to a functional block of the VGKC rather than altered structural integrity of the VGKC. Taken together, we found IgG4 aAbs to be a major modifier of potassium channel function. The increase in DRG excitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAbs binding but additional and so far unidentified signal pathways contribute to this process in patients with neuropathic pain.

neuroscience↗

bioRxiv2021

Molecular Mechanisms of Neurotransmitter Release Control Distinct Features of Sensory Coding Reliability

To survive, animals must recognize reoccurring stimuli. A key requirement for repeated identification of stimuli is reliable representation by the neural code on each encounter. Synaptic transmission underlies neural codes propagation between brain regions. A hallmark of chemical synapses is their plasticity, which enables signal transfer to be modified in an activity-dependent manner. Despite many decades of intense research on synapses, it remains unclear how the plastic features of synaptic transmission can maintain reliable neural coding. By studying the olfactory system of Drosophila melanogaster, we aimed to obtain a deeper mechanistic understanding of how synaptic function shapes neural coding reliability in the live, behaving animal. We show that the properties of the active zone (AZ), the presynaptic site of neurotransmitter release, are critical for generating a reliable neural code. Reducing neurotransmitter release probability specifically at AZs of olfactory sensory neurons disrupted both neural coding and behavioral reliability. Strikingly, these defects were rescued within a day by target-specific synaptic plasticity, whereby a homeostatic increase in the number of AZs compensated the drop in release probability. These findings demonstrate an important role for synaptic plasticity in maintaining neural coding reliability and are of pathophysiological interest by uncovering an elegant mechanism through which the neural circuitry can counterbalance perturbations.

neuroscience↗