Biology subjects

Thomale, U.-W.

Publications and source records attributed to Thomale, U.-W..

3 recordsLinked to original sources

bioRxiv2026

Differential effects of AMPA receptor inhibition on seizure-like events in murine and human brain slices

Epilepsy is a frequent neurological condition with a worldwide prevalence of 0.5-1%. Current therapies are limited by adverse effects as well as drug resistance. This highlights the need for novel, target-specific antiseizure medications with improved efficacy and fewer side effects. AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors represent a therapeutic target as demonstrated by perampanel, an AMPA receptor antagonist used clinically as antiseizure medication. AMPA receptors typically mediate fast excitatory neurotransmission. Their properties are modulated by auxiliary proteins that can alter receptor activation, deactivation and desensitization, including converting them into slow AMPA receptors. In this study, we tested different AMPA receptor inhibitors, including perampanel, for their ability to suppress seizure-like events (SLE). SLE were recorded with extracellular electrodes in cortical brain slices from healthy mice and from epilepsy patients who underwent resective surgery. SLE were induced with 4-aminopyridine (4-AP) or a combination of 4-AP and high-potassium. We found that seizure-like events in murine tissue appeared more frequently, with higher amplitude and spike frequency, but were briefer than in human tissue. GYKI53655, NBQX and perampanel were equally effective in inhibiting SLE in murine und human brain slices. In contrast, the antagonist LY3130481, specific for the AMPA receptor auxiliary protein {gamma}-8, showed only weak efficacy in murine tissue, but blocked of SLE in human tissue almost completely. The species-specific differences we found for LY3130481 highlight the benefit of using human tissue in preclinical research and underline that auxiliary subunits remain a promising therapeutic target for the development of new antiseizure medications.

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↗

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↗