Interneuron Transplantation Remodels Host Circuitry and Improves Seizure Phenotypes in an Epileptogenic Circuit Model
Abstract number :
3.049
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2025
Submission ID :
220
Source :
www.aesnet.org
Presentation date :
12/8/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Elizabeth Matthews, PhD – Duke University
Kevin Bode Padron, BS – Duke University
Michele Yeo, PhD – Duke University
Peyton Thompson, BS – Duke University
Lydia Blatnik, BS – D
Muhib Methani, BS – Duke University
Christine Park, MD – University of Washington
Derek Southwell, MD PhD – Duke University
Rationale: Interneuron precursor transplantation increases synaptic inhibition onto recipient neurons and corrects seizure phenotypes in rodent models of epilepsy. It has been hypothesized that transplanted interneurons act therapeutically by forming new, functional GABAergic synapses that restore inhibition and counter hyperexcitability in epileptogenic recipient circuits. We sought to investigate the time-course and mechanisms by which transplanted medial ganglionic eminence (MGE) interneurons integrate into existing hippocampal networks, to examine alterations in network seizure activity following transplantation, and to quantify alterations in the excitation-inhibition balance in an in vitro epileptic model.
Methods: We used organotypic mouse hippocampal slice cultures, a circuit model of epilepsy, to further investigate how synaptic inhibition and excitation are altered in the setting of transplant-mediated seizure correction. Interneuron precursors from E13.5 mouse MGE were transplanted into the hilus of the organotypic slice and allowed to integrate in culture. The migration, maturation, and integration into the host circuit were evaluated through immunohistochemistry and electrophysiological measures. The epileptic activity of the organotypic slices was monitored by MEA recordings.
Results: Transplanted MGE cells dispersed, matured, and received synaptic inputs in organotypic hippocampal slices over 28 days in culture. Transplantation likewise increased synaptic inhibition onto slice neurons and improved spontaneous seizure phenotypes in slices. Surprisingly, however, interneuron transplantation did not alter inhibitory-excitatory balance in slice neurons, as increases in synaptic inhibition were accompanied by increases in synaptic excitation. Underlying this global increase in synaptic inhibition and excitation, the intrinsic excitability and synaptic connectivity of slice neurons – both inhibitory and excitatory types – were increased in the transplant condition.
Conclusions: These results indicate that interneuron transplantation can improve seizure phenotypes without simply boosting synaptic inhibition or shifting inhibitory-excitatory balance. Transplantation drove alterations in the recipient circuitry, as reflected by increased recipient cellular excitability and synaptic connectivity. These modifications, which may reflect homeostatic responses to transplant synaptic integration, could reduce the epileptogenicity of recipient circuits. The seizure-ameliorating effect of interneuron transplantation may occur through mechanisms beyond or in addition to an increase in GABAergic tone, which is significant for the therapeutic potential of cell-based transplantation.
Funding: Ruth K Broad Foundation, Klingenstein Foundation, NIH 1DP2MH140149-01
Basic Mechanisms