Presynaptic GABABSignaling Enhances Synaptic Inhibition Without Mitigating Persistent Dentate Gyrus Hyperexcitability After Status Epilepticus
- 1University of California - Riverside
Abstract
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 GABAB 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 GABAB 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 GABAB signaling in restraining network excitability early after SE. CGP36216 robustly increased PPR at 20ms across all groups without altering DS frequency, suggesting that GABAB 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 GABAB receptors, which bolsters synaptic inhibition to transiently counter post-SE hyperexcitability, and offers a targetable mechanism for therapeutic intervention during epileptogenesis.
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BibTeX
@misc{subramanian2026presynaptic,
title = {{Presynaptic GABABSignaling Enhances Synaptic Inhibition Without Mitigating Persistent Dentate Gyrus Hyperexcitability After Status Epilepticus}},
author = {D. Subramanian and S. Ratnadurai Giridharan and A. Irfan and V. Santhakumar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752988},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752988v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Presynaptic GABABSignaling Enhances Synaptic Inhibition Without Mitigating Persistent Dentate Gyrus Hyperexcitability After Status Epilepticus
AU - D. Subramanian
AU - S. Ratnadurai Giridharan
AU - A. Irfan
AU - V. Santhakumar
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.752988
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.752988v1
AB - 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 GABAB 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 GABAB 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 GABAB signaling in restraining network excitability early after SE. CGP36216 robustly increased PPR at 20ms across all groups without altering DS frequency, suggesting that GABAB 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 GABAB receptors, which bolsters synaptic inhibition to transiently counter post-SE hyperexcitability, and offers a targetable mechanism for therapeutic intervention during epileptogenesis.
ER -