Biology subjects

Fidzinski, P.

Publications and source records attributed to Fidzinski, P..

7 recordsLinked to original sources

bioRxiv2026

Acute exposure of mouse and human hippocampal slices to tau oligomers reversibly impairs sharp-wave ripples

Sharp-wave ripple (SWR) oscillations are crucial for memory consolidation and deteriorate in Alzheimers disease (AD). Tau oligomers are suggested to lead to synaptic and neuronal degeneration in AD, but their effects on SWRs are unknown. To study this, we prepared mouse and human hippocampal slices and bath-applied tau oligomer preparations after spontaneous SWR generation. In human slices, acute exposure to tau resulted in decreased ripple duration, whereas in mouse slices it was SWR rate, amplitude, and power that decreased, sparing duration. In a different set of experiments, mouse slices were pre-incubated directly in either tau-ACSF or control-ACSF right after slicing for 2.5-5.5 hours, resulting only in diminished SWR rate. These effects were specific to the presence of {beta}-sheets, as a different tau preparation that lacked {beta}-sheets failed to alter SWRs. This method is therefore suitable to study SWR alterations after short-term exposure to different tau and/or A{beta} species, allows a higher throughput screening of possible therapeutics compared to in vivo animal experiments, and permits direct comparison of SWR alterations in mice and humans.

neuroscience↗

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↗

bioRxiv2026

Mind the translational gap: human microglia differ from mouse microglia in their regulation of Kv and Kir2.1 channels

K+ channels are important for controlling membrane potential and regulating functional properties of microglia. Whereas the inward-rectifying K+ (Kir) channel 2.1 modulates proliferation, voltage-gated K+ channels (Kv) are linked to inflammatory response in mouse microglia (mMG). These channels serve as possible drug targets but little is known regarding their activity in human microglia. We used patch-clamp recording to study membrane currents of primary human microglia (hMG) and human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MGL) and compared them with mMG. Unlike mMG, hMG and hiPSC-MGL exhibited Kir2.1 currents only after LPS+IFN-{gamma} stimulation. Interestingly, Kv currents were not observed in hMG or hiPSC-MGL under any condition. While mMG had a progressively ameboid morphology after stimulation, hMG showed few morphological changes and hiPSC-MGL increased ramification. Overall, the activity of Kir2.1 and Kv channels in hMG and hiPSC-MGL differs fundamentally from mMG. Our findings highlight differences between species and underscore the need for translational approaches.

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↗

bioRxiv2021

Intra-individual Physiomic Landscape of Pyramidal Neurons in the Human Neocortex

Understanding the functional principles of the human brain requires deep insight into the neuronal and network physiology. To what extent such principles of cellular physiology and synaptic interactions are common across different human individuals is unknown. We characterized the physiology of ~1200 pyramidal neurons and ~1400 monosynaptic connections using advanced multineuron patch-clamp recordings in slices from human temporal cortex. To disentangle within and between individual sources of heterogeneity, we recorded up to 100 neurons per single subject. We found that neuronal, but not synaptic physiology varied with laminar depth. Connection probability was ~15% throughout layer 2-3. Synaptic amplitudes exhibited heavy-tailed distributions with an inverse power law relationship to short term plasticity. Neurons could be classified into four functional subtypes. These general principles of microcircuit physiology were common across individuals. Our study advances the understanding of human neuron and synaptic diversity from an individual and phenotypic perspective.

neuroscience↗

bioRxiv2020

Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia

Activation of the kynurenine pathway may lead to depletion of the serotonin precursor tryptophan, which has been implicated in the neurobiology of depression. This study describes a mechanism whereby lithium inhibits inflammatory tryptophan breakdown. Upon activation, immortalized human microglia showed a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3{beta}S9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in activated cells. Experiments in primary human microglia and human induced pluripotent stem cell (hiPSC)-derived microglia corroborated lithiums effects. Moreover, IDO activity was reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705. Our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.

neuroscience↗