Long-Term Effects of Moderate Concussive Brain Injury During Adolescence on Synaptic and Tonic GABA Currents in Dentate Granule Cells and Semilunar Granule Cells.

Akshay Gupta,Laura Dovek,Archana Proddutur,Fatima S Elgammal,Vijayalakshmi Santhakumar

doi:10.3389/fnins.2022.800733

Abstract

Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury (TBI) contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, and whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, have not been evaluated. We examined long-term changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons 3 months after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to 1 month after FPI, but decreased to levels comparable with age-matched controls by 3 months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased 1 week after FPI, remained higher than in age-matched controls at 1 month and was significantly reduced 3 months after FPI. In semilunar granule cells, tonic GABA current amplitude and sIPSC frequency were not different from controls 3 months after FPI, which contrast with decreases observed 1 week after injury. The switch in granule cell inhibitory inputs from early increase to subsequent decrease could contribute to the delayed emergence of cognitive deficits and seizure susceptibility after brain injury.

Highlights

Traumatic brain injury (TBI) leads to diverse consequences including impaired memory and reasoning, depression, anxiety as well as enhanced risk for epilepsies and Alzheimer’s disease (LoBue et al, 2019; Faden et al, 2021)
While we have reported an increase in granule cells (GCs) tonic GABA currents 1 week after moderate fluid percussion injury (FPI) in 25–26-day-old rats (Gupta et al, 2012), a period that parallels human adolescence in terms of neurological developmental (Semple et al, 2013; Sengupta, 2013), no changes in GC tonic GABA currents were observed 1–5 months after severe FPI in adult rats (Pavlov et al, 2011)
To determine the time course of changes in tonic GABA currents after developmental FPI, we examined GCs from rats injured during adolescence at two time points: 1 and 3–4 months post-FPI

Summary

Introduction

Traumatic brain injury (TBI) leads to diverse consequences including impaired memory and reasoning, depression, anxiety as well as enhanced risk for epilepsies and Alzheimer’s disease (LoBue et al, 2019; Faden et al, 2021). Strong synaptic and extrasynaptic inhibition of dentate granule cells (GCs) contributes to their sparse activity and is known to be disrupted in TBI and epilepsies (Peng et al, 2004; Rajasekaran et al, 2010; Pavlov et al, 2011; Gupta et al, 2012; Boychuk et al, 2016; Kahn et al, 2019; Parga Becerra et al, 2021). We previously reported an increase in GC synaptic and tonic GABA currents 1 week after moderate concussive brain injury in adolescent rats (Gupta et al, 2012). This clinically relevant adolescent concussive injury paradigm impairs working memory performance 1–4 weeks postinjury followed by heightened risk for seizures 1–3 months after injury (Neuberger et al, 2017b; Korgaonkar et al, 2020a,b). Since GABAergic signaling, which critically regulates dentate memory function and epileptogenesis (Dengler and Coulter, 2016), undergoes developmental plasticity spanning in this period (Kapur and Macdonald, 1999; Gupta et al, 2020), we sought to determine if GC inhibition undergoes progressive changes after concussive TBI

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