Traumatic Brain Injury Broadly Affects GABAergic Signaling in Dentate Gyrus Granule Cells

Abstract

Traumatic brain injury (TBI) causes cellular and molecular alterations that contribute to neuropsychiatric disease and epilepsy. GABAergic dysfunction figures prominently in the pathophysiology of TBI, yet the effects of TBI on tonic inhibition in hippocampus remain uncertain. We used a mouse model of severe TBI (controlled cortical impact, CCI) to investigate GABAergic signaling in dentate gyrus granule cells (DGGCs). Basal tonic GABA currents were not affected by CCI. However, tonic currents induced by the δ subunit-selective GABA A receptor agonist THIP (10 µM) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent 1 week after injury and persisted up to 15 weeks. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABA A receptor δ subunits and GABA B receptor B2 subunits after CCI, by 43% and 40%, respectively. Activation of postsynaptic GABA B receptors caused a 2-fold increase in tonic currents, and this effect was markedly attenuated in CCI-ipsi cells (92% reduction). GABA B receptor-activated K + currents in DGGCs were also significantly reduced in CCI-ipsi cells, confirming a functional deficit of GABA B receptors after CCI.Results indicate broad disruption of GABAergic signaling in DGGCs after CCI, with deficits in both phasic and tonic inhibition and GABA B receptor function. These changes are predicted to disrupt operation of hippocampal networks and contribute to sequelae of severe TBI, including epilepsy. 3 Significance statementTraumatic brain injury (TBI) causes cellular and molecular changes that contribute to the clinical sequelae of TBI, including epilepsy, cognitive deficits, and mood disorders. Improved understanding of these cellular and molecular changes will inform therapeutic approaches to potentially disrupt epileptogenesis and treat symptoms. We investigated changes in GABAergic signaling of dentate gyrus granule cells (DGGCs) in a preclinical model of severe TBI (controlled cortical impact) and identified early and persistent deficits in expression and function of both synaptic and extrasynaptic GABA A receptors and GABA B receptors. These broad changes in GABAergic signaling will alter function of DGGCs and are predicted to perturb hippocampal networks and contribute to epileptogenesis and cognitive deficits after TBI.

Long-term effects of moderate concussive brain injury during adolescence on synaptic and tonic GABA currents in dentate projection neurons

“…Tonic and synaptic GABA currents are known to be altered after brain injury with outcomes varying between experimental models. GC tonic GABA current amplitude was reported to be similar to controls 2-20 weeks after murine CCI or severe concussion in adult rats (Pavlov et al, 2011; Boychuk et al, 2016; Parga Becerra et al, 2021) which contrasts with the increase we had reported one week after moderate concussion in adolescent rats (Gupta et al, 2012). Our current demonstration that GC tonic GABA current amplitude remains elevated one month after injury differs from Pavlov et al (2011) and parallels our observation at one week (Gupta et al, 2012), while the recover to control levels by three months is consistent with Pavlov et al (2011).…”

“…Tonic GABA currents mediated by extrasynaptic receptors contribute to reduced GC excitability (Stell et al, 2003; Brickley and Mody, 2012). Granule cell tonic GABA currents are altered in experimental brain injury (Gupta et al, 2012; Boychuk et al, 2016; Parga Becerra et al, 2021). We previously reported a potentially beneficial increase in GC tonic GABA currents one week after moderate FPI 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).…”

“…TBI results in diverse cellular and network alteration (Morales et al, 2005; Pitkanen et al, 2009; Hunt et al, 2013; Neuberger et al, 2017a). Acute injury-induced death of GABAergic neurons in the dentate hilus initiates progressive changes in inhibition which differ between injury models (Lowenstein et al, 1992; Toth et al, 1997; Hunt et al, 2011; Pavlov et al, 2011; Frankowski et al, 2019; Parga Becerra et al, 2021). Our data identify progressive changes in tonic and synaptic GABA currents, which differ between the GCs and SGCs.…”

“…TBI is a lifelong disease with adverse outcomes that evolve over months to years, highlighting the need to understand progressive changes in cellular and circuit function following brain injury (Marshall et al, 2015). The hippocampal dentate gyrus is a focus of cellular pathology and functional changes following brain injury in humans and various experimental models of TBI (Kharatishvili et al, 2006; Hunt et al, 2010; Villasana et al, 2015; Meier et al, 2016; Neuberger et al, 2017a; Neuberger et al, 2017b; Wolf et al, 2017; Parga Becerra et al, 2021). The dentate gyrus is a crucial gateway to the hippocampal circuit, serving as a locus for memory processing and as a check against excessive excitability and reentrant epileptiform activity (Dengler and Coulter, 2016).…”

“…The dentate gyrus is a crucial gateway to the hippocampal circuit, serving as a locus for memory processing and as a check against excessive excitability and reentrant epileptiform activity (Dengler and Coulter, 2016). Strong synaptic and extrasynaptic inhibition of dentate projection neurons 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). Studies examining injury-induced changes in inhibition in dentate granule cells (GCs), the major projection neuronal subtype, days to weeks after trauma have identified changes in synaptic and extrasynaptic GABA A currents which differ between experimental injury models and on the basis of injury severity (Santhakumar et al, 2001; Pavlov et al, 2011; Gupta et al, 2012; Boychuk et al, 2016).…”