Pressynaptyczne sygnały GABA_B wzmacniają hamowanie synaptyczne, ale nie eliminują trwałej nadpobudliwości zęba hipokampu po stanie padaczki
Presynaptic GABA <sub>B</sub> Signaling Enhances Synaptic Inhibition Without Mitigating Persistent Dentate Gyrus Hyperexcitability After Status Epilepticus
W skrócie
[Preprint - wstępne wyniki] Badacze badali zmiany w aktywności części mózgu zwanej zębem hipokampu u szczurów po ciężkim ataku padaczki. Odkryli, że receptory GABA_B na neuronach hamujących mogą czasowo zmniejszać nadpobudliwość mózgu w pierwszych tygodniach, ale nie mogą całkowicie zatrzymać długotrwałych zmian padaczki trwających wiele miesięcy. Wyniki sugerują, że receptory te mogą być potencjalnym celem do leczenia padaczki na wczesnych etapach jej rozwoju.
Oryginalny abstract (angielski)
The dentate gyrus (DG) is a critical regulator of cortical input processing in the hippocampus, supporting spatial navigation and memory processing. In epilepsy, the DG undergoes extensive structural and functional reorganization that diminishes its ability to filter afferent inputs, resulting in enhanced hippocampal hyperexcitability, seizures, and cognitive impairment. Yet, how DG network dynamics evolve over time in the epileptic brain is not fully understood. Here, we investigated DG network excitability, feedback inhibition, and throughput in rats 1 week, 8 weeks, and 4 months after pilocarpine-induced status epilepticus (SE), and examined the role of presynaptic GABA B receptor-mediated modulation of DG activity. Recording from urethane-anesthetized rats in vivo, we show a persistent increase in excitation-spike (E-S) coupling after SE. In contrast, feedback inhibition measured by short-duration paired-pulse ratios (PPR at 20ms, 40 ms and 60ms intervals) was significantly increased 1 and 8 weeks after SE, but was indistinguishable from controls by 4 months. Notably, we found that dentate spike (DS) frequency remained persistently elevated up to 10 months post-SE. Selective inhibition of presynaptic GABA B receptors in the DG using CGP36216 further enhanced E-S coupling at 1 and 8 weeks in post-SE rats without affecting age-matched controls. CGP36216 did not alter E-S coupling in rats 4 months after SE, revealing a homeostatic role for basal presynaptic GABA B signaling in restraining network excitability early after SE. CGP36216 robustly increased PPR at 20ms across all groups without altering DS frequency, suggesting that GABA B receptors boost DG feedback inhibition. Mechanistically, CGP36216 reduced single stimulus-evoked inhibitory postsynaptic currents (eIPSCs) in dentate granule cells without altering excitatory transmission after SE. Together, these findings support a disinhibitory role for presynaptic GABA B receptors, which bolsters synaptic inhibition to transiently counter post-SE hyperexcitability, and offers a targetable mechanism for therapeutic intervention during epileptogenesis.