Biology subjects

Tiszlavicz, A.

Publications and source records attributed to Tiszlavicz, A..

5 recordsLinked to original sources

bioRxiv2026

Cariprazine modulates intrinsic excitability and network dynamics of hippocampal neurons in a cell-type dependent manner

Schizophrenia is a severe psychiatric disorder associated with altered dopaminergic signaling and hippocampal circuit dysfunction. Although antipsychotic medications remain the standard treatment, many are limited by incomplete efficacy and adverse effects. Cariprazine, a dopamine D2/D3 receptor partial agonist, has a favorable clinical profile, but its effects on neuronal excitability and network activity remain incompletely understood. Here, we integrated nationwide real-world clinical data with in vitro electrophysiology, computational modeling, and molecular analyses to define the neuronal actions of cariprazine. Among Hungarian patients diagnosed with schizophrenia and receiving index-drug monotherapy with one of the three prespecified D2/D3 targeting antipsychotics, haloperidol was associated with worse survival and a higher cumulative incidence of first registered suicide attempt than cariprazine or aripiprazole in matched observational cohorts. In primary mouse hippocampal cultures, multielectrode array recordings showed that acute cariprazine treatment moderately reduced spontaneous firing in a dose-dependent manner and prolonged burst intervals while largely preserving network synchronization. These effects were milder than those of haloperidol and aripiprazole. Whole-cell patch-clamp recordings revealed cell-type-dependent effects, with reduced intrinsic excitability and increased firing irregularity mainly in regular- and stuttering-type neurons. Conductance-based modeling identified enhanced Kv1-mediated D-type potassium currents as sufficient to reproduce these effects. Consistent with this mechanism, chronic cariprazine treatment altered Kv1.2 protein distribution without changing Kcna2/Kcna3 or Drd1/Drd2/Drd3 transcript expression. These findings identify modulation of intrinsic excitability via Kv1/D-type potassium currents as a candidate cellular mechanism of cariprazine and provide a translational link between real-world evidence and circuit-level drug effects.

neuroscience↗

bioRxiv2025

Regulation of input excitability in human and mouse parvalbumin interneurons by Kir potassium channels

Compared to rodents, inhibitory interneurons in the human neocortex exhibit high input excitability because of reduced passive ion leakage across their extracellular membrane. However, the regulation of intrinsic excitability by voltage-gated ion channels activated over a wide range of membrane potentials in human interneurons remains poorly understood. We performed whole-cell patch-clamp microelectrode recordings in mouse and human neocortical slices obtained from surgically resected non-pathological brain tissue finding that Kir channels control the electrical resistance of parvalbumin (Pvalb) neurons in an identical manner in the human and mouse. Molecular analyses revealed predominantly Kir3.1 and Kir3.2 channels in Pvalb neurons in both species. Using whole-cell recordings from synaptically connected neuron pairs and a computational model, we demonstrated that physiological Kir activation inhibits human Pvalb interneurons during postsynaptic potentials evoked by presynaptic neurogliaform cells. The similarity of Kir-mediated inhibition across species suggests that it is an archetypal property of Pvalb neurons.

neuroscience↗

bioRxiv2024

Mechanisms and purpose of lowered action potential firing threshold in fast-spiking interneurons in the human neocortex

The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage-activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in-fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast- spiking neurons, it is crucial to take into account the molecular and functional species differences. Short blurb: Fast-spiking neurons in the human neocortex feature structural and molecular specializations in the axon initial segment that lower firing thresholds and minimize input- output delay.

neuroscience↗

bioRxiv2024

Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms

Previous studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8{degrees}C higher than the external environment (40{degrees}C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.

cell biology↗

bioRxiv2024

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex

Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11-84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.

neuroscience↗