Biology subjects

Geiger, J. R.

Publications and source records attributed to Geiger, J. R..

7 recordsLinked to original sources

bioRxiv2026

Syncytial coupling of mid-capillary pericytes underlies seizure-associated electro-metabolic signaling

Disturbances of neurovascular coupling (NVC) contribute to metabolic derailment and neurological symptoms associated with epilepsy. While postictal arterial constriction can be alleviated by inhibitors of voltage gated calcium channels (VGCCs), less is knownregarding seizure-associated electrical signals in higher-order capillaries and their role in determining pericyte tone during seizures. Here we investigated electrical signaling within the ex vivo neurovascular unit (NVU) derived from rat and human brain tissue. We focused on electrical signal transduction between pericytes and endothelial cells and the potential role of VGCCs in vasomotion. Using dye coupling and paired patch-clamp recordings, we showed that morphologically heterogeneous groups of mid-capillary pericytes build a functional syncytium with endothelial cells. Coupling was asymmetric, allowing for directed propagation of electrical signals. Regardless of their morphology, mid-capillary pericytes responded with depolarization and constriction to metabotropic receptor (GPCR) activation (by thromboxane, norepinephrine and UDP-glucose). However, depolarization via the patch pipette induced neithe r Ca2+-influx nor constriction, suggesting lack of contribution of VGCCs to vasomotion. On inducing epileptiform activity, A2a adenosine receptors and inwardly rectifying potassium channels hyperpolarized the capillary syncytium, followed by repeated depolarizations due to seizure-associated potassium increase in the parenchyma. Thus, while mid-capillary pericytes are contractile, their tone does not rely on their membrane potential and VGCCs. However, syncytial coupling allows for transmission of seizure-associated hyper- and depolarizing signals to upstream feeding arterioles.

neuroscience↗

bioRxiv2025

The polyamine naphthyl-acetyl spermine trihydrochloride (NASPM) lacks specificity for Ca2+-permeable AMPA receptors and suppresses seizure like activity in human brain tissue by inhibition of NMDA receptors.

For decades, naphthyl-acetyl spermine trihydrochloride (NASPM) has been used as a selective inhibitor of calcium-permeable AMPA receptors (CP-AMPAR). In rodents, NASPM is known to suppress seizures in vivo and seizure-like events (SLE) in vitro, suggesting possible involvement of CP-AMPAR in ictogenesis and epileptogenesis. To address whether these findings can be translated to human brain, we investigated the involvement of glutamatergic receptor subclasses in SLE in human cortex ex vivo, demonstrating that glutamatergic receptor antagonists can block (NASPM and APV) or reduce (UBP302, GYKI52466, GYKI53655) SLE. Using a multimethodological approach we were able to demonstrate that both NASPM and APV inhibit human SLE by inhibition of NMDA receptors. Our results further show that the inhibitory effect of NASPM on NMDA receptors is sufficient to explain its inhibition of seizure like activity, rather than its action on CP-AMPA receptors. Thus, our findings challenge previous knowledge on the use of NASPM as a specific CP-AMPAR inhibitor. Some phenomena previously attributed to CP-AMPAR, may need to be re-examined more closely. Overall, our study raises awareness about potential pitfalls in the use of existing pharmacological agents and sets a new paradigm for the use of NASPM in neuroscience research while questioning its therapeutic potential in a clinical context.

neuroscience↗

bioRxiv2024

The functional impact of LGI1 autoantibodies on human CA3 pyramidal neurons

Autoantibodies against leucine-rich glioma inactivated 1 protein (LGI1 mAb) lead to limbic encephalitis characterized by seizures and memory deficits. While animal models provide insights into mechanisms of LGI1 mAb action, species-specific confirmation is lacking. In this study, we investigated the effects of patient-derived LGI1 mAb on human CA3 neurons using cultured ex vivo slices. Analysis of intrinsic properties and morphology indicated functional integrity of these neurons under incubation conditions. Human CA3 neurons received spontaneous excitatory currents with large amplitudes and frequencies, suggestive of "giant" AMPA currents. In slices exposed to LGI1 mAb, human CA3 neurons displayed increased neuronal spike frequency, mirroring effects observed with the Kv1.1 channel blocker DTX-K. This increase likely resulted from decreased Kv1.1 channel activity at the axonal initial segment, as indicated by alterations in action potential properties. A detailed analysis revealed differences between LGI1 mAb and DTX-K effects on action potential properties, suggesting distinct mechanisms of action and emphasizing the need for further exploration of downstream pathways. Our findings underscore the importance of species-specific confirmatory studies of disease mechanisms and highlight the potential of human hippocampal slice cultures as a translational model for investigation of disease mechanisms beyond epilepsy, including the effects of pharmacological compounds and autoantibodies. SignificanceThis study advances our understanding of how autoantibodies against the LGI1 protein, known to cause limbic encephalitis, impact human neurons. By using cultured slices of human hippocampus derived from epilepsys surgical resections, we were able to observe the direct effects of these autoantibodies on neurons, specifically CA3 pyramidal cells. Our findings reveal that the autoantibodies increase neuronal activity, similar to what is seen with potassium channel blockers and in animal models. This work emphasizes the importance of studying living tissue from the human brain to confirm disease mechanisms, and demonstrates the potential of using human brain slices as a model for exploring not only epilepsy but also other neurological diseases and drug effects.

neuroscience↗

bioRxiv2023

Gamma-Oscillation Plasticity Is Mediated by Parvalbumin Interneurons

Understanding the plasticity of neuronal networks is an emerging field of (patho-)physiological research, yet little is known about the underlying cellular mechanisms. Gamma-oscillations (30 - 80 Hz), a biomarker of cognitive performance, require and potentiate glutamatergic transmission onto parvalbumin-positive interneurons (PVIs), suggesting an interface for cell-to-network plasticity. In ex vivo local field potential recordings, we demonstrate long-term potentiation of hippocampal gamma-power. Gamma-potentiation obeys established rules of PVI plasticity, requiring calcium-permeable AMPA receptors (CP-AMPARs) and metabotropic glutamate receptors (mGluRs). A microcircuit model of CA3 gamma-oscillations predicts CP-AMPAR plasticity onto PVIs critically outperforms pyramidal cell plasticity in increasing gamma-power and completely accounts for gamma-potentiation. We re-affirm this ex vivo in three PVI-targeting animal models, demonstrating that gamma-potentiation requires PVI-specific metabotropic signaling via a Gq/PKC-pathway comprising mGluR5 and a Gi-sensitive, PKA-dependent pathway. Gamma-activity dependent, metabotropically mediated CP-AMPAR plasticity on PVIs may serve as a guiding principle in understanding network plasticity in health and disease.

neuroscience↗

bioRxiv2022

Coherent network oscillations regulate quiescence and behavioral responsiveness in Drosophila

For all animals, undisturbed periods of rest are essential for undergoing recuperative processes. How neural interactions create brain states capable of dissociating an animal from its external world to promote quiescence remains a fundamental question. Here, we show how coherent network oscillations can create neural filters that favor a quiescent brain state over a state that promotes navigation. Circadian regulation and excitability of the Drosophila sleep homeostat (dFSB) generate nighttime specific slow-wave coherence between neural networks mediating sleep need (R5) and networks gating locomotion (helicon cells). Optogenetically mimicking coherent activity reveals that temporally fine-tuned R5 oscillations promote a quiescent state and reduce responsiveness to visual stimuli by hierarchically overruling locomotion-promoting helicon cells. We uncover that R5 and helicon bidirectionally regulate behavioral responsiveness by providing antagonistic inputs to head direction targets (EPG). Thus, coherent oscillations can form the mechanistic basis of neural filters by temporally associating antagonistic inputs and therefore reducing the functional connectivity between locomotion gating and navigational networks.

neuroscience↗

bioRxiv2021

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. ResultsExcitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation, but not SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

neuroscience↗

bioRxiv2019

High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

Comparing neuronal microcircuits across different brain regions, species and individuals can reveal common and divergent principles of network computation. Simultaneous patch-clamp recordings from multiple neurons offer the highest temporal and subthreshold resolution to analyse local synaptic connectivity. However, its establishment is technically complex and the experimental performance is limited by high failure rates, long experimental times and small sample sizes. We introduce an in-vitro multipatch setup with an automated pipette pressure and cleaning system facilitating recordings of up to 10 neurons simultaneously and sequential patching of additional neurons. We present hardware and software solutions that increase the usability, speed and data throughput of multipatch experiments which allowed probing of 150 synaptic connections between 17 neurons in one human cortical slice and screening of over 600 connections in tissue from a single patient. This method will facilitate the systematic analysis of microcircuits and allow unprecedented comparisons at the level of individuals.

neuroscience↗