Biology subjects

Goetz, T.

Publications and source records attributed to Goetz, T..

5 recordsLinked to original sources

bioRxiv2026

Anti-GABAB receptor autoimmunity causes cognitive decline by presynaptic pathology

The GABAB receptor is a central regulator of neuronal transmission and excitability by pre- and postsynaptic mechanisms. Its dysfunction causes severe neurological disease, but the underlying pathomechanisms remain elusive. Here, we exploit a distinct CNS autoimmune disorder in which patients develop specific autoantibodies against GABAB receptors causing autoimmune encephalitis with severe memory dysfunction and epilepsy. We demonstrate that human autoantibodies target the sushi-domains of the GABAB receptor B1a subunit and the B2 subunit and interfere with presynaptic signaling. This specific presynaptic pathology results from exclusive functional antagonism of the B1a subunit and disrupts short- and long-term synaptic plasticity, abnormally amplifies hippocampal network oscillations and coupling in vivo, and ultimately impairs memory consolidation. Our results demonstrate that autoimmune presynaptic pathomechanisms alone are sufficient to interfere with memory processing, thus defining a causal link between molecular GABAB receptor disturbance, synaptic pathology, circuit dysfunction, and dementia distinct from classical neurodegenerative processes.

neuroscience↗

bioRxiv2025

Active zone remodeling by Bruchpilot couples synaptic architecture to Kv1/Shaker excitability control

Presynaptic active zones are known to undergo state-dependent remodeling across sleep, circadian, and experience-dependent conditions, yet how such structural changes influence synaptic computation and excitability has remained unclear. Here, we address this gap by examining the functional consequences of physiological upscaling of the active zone scaffold Bruchpilot (BRP), within the range previously observed during natural state-dependent plasticity. We show that moderate BRP elevation expands the number of functional release sites while surprisingly reducing vesicle release probability, thereby establishing a presynaptic operating mode with selectively enhanced transmission at intermediate firing frequencies. This remodeled mode depends on Kv1/Shaker potassium channels, which normally constrain the increased structural capacity generated by BRP; accordingly, perturbation of Shaker abolishes BRP-dependent reductions in release probability and unmasks an enlarged synaptic output capacity. To test the functional relevance of this coupling, we examined sleepless mutants, in which Kv1/Shaker channels are destabilized and presynaptic remodeling is compromised. We show that direct, physiological-level BRP upscaling selectively restores the Shaker/Hyperkinetic channel complex from near-undetectable levels toward normal abundance without inducing global proteomic changes, and correspondingly rescues excitability balance, oxidative stress resistance, lifespan, and mid-term memory. Together, these findings identify a mechanistic coupling between active zone architecture and intrinsic excitability control and demonstrate how presynaptic structural plasticity shapes frequency-dependent transmission and functional robustness under stress.

neuroscience↗

bioRxiv2025

Monoamine-induced diacylglycerol signaling rapidly accumulates Unc13 in nanoclusters for fast presynaptic potentiation

Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein coupled receptors. Long-term potentiation of presynaptic neurotransmitter release requires structural changes, but how fast potentiation is achieved within minutes remains enigmatic. Using the Drosophila melanogaster neuromuscular junction, we show that on the timescale of one minute, octopamine, the invertebrate analog of nor-epinephrine, rapidly potentiates evoked neurotransmitter release by a G protein coupled pathway involving presynaptic OAMB receptors and phospholipase C. No changes of presynaptic calcium influx were seen, but confocal signals of the release factor Unc13A and the scaffolding protein Bruchpilot increased within one minute of octopamine treatment. On the same timescale, live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and its increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation and removal of its N-terminal localization sequence delocalized the protein fragment to the cytosol, but it was rapidly recruited to the plasma membrane by DAG analog phorbol esters and octopamine, pointing to a role in C-terminal domains. Point mutation of endogenous Unc13 disrupting diacylglycerol-binding to its C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester-induced potentiation, decreased the calcium-sensitivity of neurotransmission and caused short-term synaptic depression. At the organismal level, the mutation reduced locomotion and survival while enhancing reproduction. Thus, the Unc13 C1 domain mediates acute subsynaptic compaction of Unc13 under monoamine-induced potentiation and influences short-term plasticity, locomotion, reproduction, and survival.

neuroscience↗

bioRxiv2024

Identification and characterization of a synaptic active zone assembly protein

At presynaptic active zones (AZs), scaffold proteins play a crucial role in coordinating synaptic vesicle (SV) release and forming intricate nanoarchitectures essential for synaptic function. Despite their suspected importance, factors governing the assembly of nanoscale AZ scaffolds have remained elusive. Here, we identify "Blobby" as a novel regulator of AZ nanopatterning, localized within the AZ scaffold. Genetic loss of the extended Blobby protein led to aberrant accumulation of AZ scaffold proteins ("blobs") and disrupted the nanoscale architecture of the AZ scaffold, resulting in a significant reduction in the packing density of voltage-gated Ca2+ channels at AZs, as observed through intravital single-molecule imaging. This disruption correlated with decreased evoked synaptic currents and SV release probability. Our findings suggest that Blobby plays a crucial role in switching the AZ scaffold into a state which allows to fine-tune the dynamic nanopatterning of Ca2+ channels to maintain proper release.

neuroscience↗

bioRxiv2020

Rules of nature's Formula Run: Muscle mechanics during late stance is the key to explaining maximum running speed

The maximum running speed of legged animals is one evident factor for evolutionary selection--for predators and prey. Therefore, it has been studied across the entire size range of animals, from the smallest mites to the largest elephants, and even beyond to extinct dinosaurs. A recent analysis of the relation between animal mass (size) and maximum running speed showed that there seems to be an optimal range of body masses in which the highest terrestrial running speeds occur. However, the conclusion drawn from that analysis--namely, that maximum speed is limited by the fatigue of white muscle fibres in the acceleration of the body mass to some theoretically possible maximum speed--was based on coarse reasoning on metabolic grounds, which neglected important biomechanical factors and basic muscle-metabolic parameters. Here, we propose a generic biomechanical model to investigate the allometry of the maximum speed of legged running. The model incorporates biomechanically important concepts: the ground reaction force being counteracted by air drag, the leg with its gearing of both a muscle into a leg length change and the muscle into the ground reaction force, as well as the maximum muscle contraction velocity, which includes muscle-tendon dynamics, and the muscle inertia--with all of them scaling with body mass. Put together, these concepts characteristics and their interactions provide a mechanistic explanation for the allometry of maximum legged running speed. This accompanies the offering of an explanation for the empirically found, overall maximum in speed: In animals bigger than a cheetah or pronghorn, the time that any leg-extending muscle needs to settle, starting from being isometric at about midstance, at the concentric contraction speed required for running at highest speeds becomes too long to be attainable within the time period of a leg moving from midstance to lift-off. Based on our biomechanical model we, thus, suggest considering the overall speed maximum to indicate muscle inertia being functionally significant in animal locomotion. Furthermore, the model renders possible insights into biological design principles such as differences in the leg concept between cats and spiders, and the relevance of multi-leg (mammals: four, insects: six, spiders: eight) body designs and emerging gaits. Moreover, we expose a completely new consideration regarding the muscles metabolic energy consumption, both during acceleration to maximum speed and in steady-state locomotion.

zoology↗