Electrical Stimulation as a Regenerative Strategy for Traumatized Hippocampal Neural Networks: From Organotypic Culture Models to Synaptic Plasticity and Axonal Growth Inhibitor Pathways

David Aphkhazava; Cezar Goletiani; Nino Nebieridze; Giorgi Gabisonia; Nodar Mitagvaria; Levan Gulua; Maka Buleishvili; Lolita Shengelia; Iuri Migriauli; Ketevan Chakhnashvili; Maka Buleishvili; Nodar Sulashvili; Mzia Tsiklauri; Manana Makharadze; Tamar Okropiridze

Authors

David Aphkhazava PhD, Professor, Alte University, Tbilisi, Georgia. Orcid: https://orcid.org/0000-0001- 6216-6477
Cezar Goletiani Professor at Free University of Tbilisi, Tbilisi, Georgia, Head scientist at Agricultural University of Georgia, Tbilisi, Georgia
Nino Nebieridze Associate Professor at Free University of Tbilisi, Tbilisi, Georgia
Giorgi Gabisonia Dean of the International School of Medicine at Alte University, Tbilisi, Georgia
Nodar Mitagvaria Ivane Beritasvili Center of Eperimental Biomedicine, Tbilisi, Georgia
Levan Gulua PhD, Professor, Head of bachelor program of Biomedicine at University of Georgia, Tbilisi, Georgia
Maka Buleishvili PhD, Invited lecturer of Georgian National University, Tbilisi, Georgia; Invited lecturer of Georgian American University, Tbilisi, Georgia
Lolita Shengelia PhD, Invited lecturer of Georgian National University, Tbilisi, Georgia; Invited lecturer of Georgian American University, Tbilisi, Georgia
Iuri Migriauli Alte University, Tbilisi, Georgia
Ketevan Chakhnashvili Clinical Director at Pineo Medical Ecosystem. Vice Dean of School of Medicine at Grigol Robakidze University. Tbilisi, Georgia
Maka Buleishvili MD, PhD, Doctor of Medical Sciences, Professor, Dean of Faculty of Medicine of BAU International University Batumi, Professor of Faculty of Medicine at European University, Professor of Faculty of Medicine at Georgian National University SEU, Professor of Faculty of Medicine at Sulkhan-Saba Orbeliani University, Invited Professor of Faculty of Healthcare Sciences at East European University, Invited Professor of Faculty of Medicine at Caucasus International University, Invited Lecturer of Tbilisi State Medical University, Tbilisi, Georgia; https://orcid.org/0009-0004-2657-8473
Nodar Sulashvili MD, PhD, Doctor of Pharmaceutical and Pharmacological Sciences In Medicine, Invited Lecturer (Professor) of Scientific Research-Skills Center at Tbilisi State Medical University; Professor of Medical and Clinical Pharmacology of International School of Medicine at Alte University; Professor of Pharmacology of Faculty of Medicine at Georgian National University SEU, Associate Affiliated Professor of Medical Pharmacology of Faculty of Medicine at Sulkhan-Saba Orbeliani University; Associate Professor of Medical Pharmacology at School of Medicine at David Aghmashenebeli University of Georgia; Associate Professor of Biochemistry and Pharmacology Direction of School of Health Sciences at the University of Georgia. Associate Professor of Pharmacology of Faculty of Dentistry and Pharmacy at Tbilisi Humanitarian Teaching University; Tbilisi, Georgia; Orcid: https://orcid.org/0000-0002-9005-8577.
Mzia Tsiklauri PhD, Affiliated Professor of the Medical Programs of Gr.Robakidze University, Microbiology, Immunology, Virology, Infection Control.Invited Professor of the Medical Programs of Alte University, Tbilisi, Georgia. Invited Professor of the Medical Programs of Caucasus International University, Laboratory Medicine, Tbilisi, Georgia. Member of the Georgian Immunologists Association, Member of the Accreditation Council of the Quality Development, Center of the Ministry of Education of Georgia
Manana Makharadze Prof. David Agmashenebeli University of Georgia, Tbilisi, Georgia.
Tamar Okropiridze MD, PhD, Doctor Medical Sciences, Academician, Professor of the Division of Dentistry of International School of Medicine at Alte University; Invited Professor of Dentistry Department of The School of Health Sciences at The University of Georgia, Tbilisi, Georgia;

Keywords:

Traumatic Brain Injury, Hippocampus, Organotypic Slice Culture, Electrical Stimulation, Multi-Electrode Array, NgR1, Synaptic Plasticity, Axonal Regeneration

Abstract

Traumatic brain injury (TBI) represents a pervasive global health burden with profound long-term neurological sequelae, particularly affecting the hippocampus, a structure critical for memory and exquisitely vulnerable to excitotoxic and inflammatory insults. This review synthesizes current knowledge regarding the pathophysiology of hippocampal injury and evaluates emerging regenerative strategies that combine electrophysiological modulation with molecular intervention. We examine the utility of organotypic hippocampal slice cultures (OHSCs) as a biologically faithful platform for modeling the secondary injury cascade, including glutamate-mediated excitotoxicity and the neuroinflammatory response. Special emphasis is placed on the disruption of Long-Term Potentiation (LTP) and adult neurogenesis as functional correlates of post-traumatic cognitive decline. We further explore the therapeutic potential of theta-burst electrical stimulation (TBS) to rescue synaptic plasticity, monitored longitudinally via non-invasive multi-electrode array (MEA) technology. Crucially, this review addresses the molecular barriers to regeneration imposed by the myelin-associated inhibitory environment—specifically Nogo-A, Myelin-Associated Glycoprotein (MAG), and Oligodendrocyte Myelin Glycoprotein (OMgp)—and their convergence upon the Nogo-66 Receptor (NgR1) signaling axis. The activation of the RhoA/ROCK pathway and subsequent growth cone collapse is discussed as a primary target for intervention. Finally, we propose a synthesis of strategies employing electrical stimulation to drive synaptic efficacy alongside pharmacological inhibition of the NgR1 axis to promote structural regrowth, assessed via key regenerative markers such as MAP2, synaptophysin, and βIII-tubulin.

Electrical Stimulation as a Regenerative Strategy for Traumatized Hippocampal Neural Networks: From Organotypic Culture Models to Synaptic Plasticity and Axonal Growth Inhibitor Pathways

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