Original research articleSelective vulnerability of hippocampal interneurons to graded traumatic brain injury
Introduction
Traumatic brain injury (TBI) is a serious neurological disorder that occurs after an external mechanical force damages the brain (e.g., from a bump, blow, or jolt to the head) and afflicts nearly 6 million Americans (Centers for Disease Control and Prevention, 2015). Trauma greatly increases the risk for a number of physical, cognitive, emotional, social and psychiatric health problems, and it is one of the most common causes of medically intractable epilepsy in humans (Rao and Lyketsos, 2000; Herman, 2002; Frey, 2003; Faul et al., 2010; Centers for Disease Control and Prevention, 2015; Scholten et al., 2015). Following TBI, damaged neural circuits undergo major reorganization that includes progressive neuron loss, synaptic circuit remodeling and changes in the cellular environment (Hunt et al., 2013).
As the primary source of inhibition in the brain, GABAergic interneurons coordinate information processing within cortical circuits by precisely timing and synchronizing excitatory principal populations. Such spatiotemporal control over input-output activity is achieved by a remarkable diversity of interneurons, each with distinct molecular, anatomical and electrophysiological properties (Freund and Buzsáki, 1996; Pelkey et al., 2017). In hippocampus, deficits in interneuron number or function have been implicated in a wide range of neurodegenerative disorders, such as epilepsy (de Lanerolle et al., 1989) Alzheimer's disease (Satoh et al., 1991) and stroke (Liepert et al., 2000). Studies examining brain tissue samples from patients with TBI have also found reductions in the number of interneurons in hippocampus (Swartz et al., 2006) and neocortex (Buriticá et al., 2009). These clinical findings are supported by a growing body of experimental data using in vivo rodent TBI models that display reductions in GABAergic neurons (Lowenstein et al., 1992; Toth et al., 1997; Santhakumar et al., 2000; Gupta et al., 2012; Cantu et al., 2015; Huusko et al., 2015; Butler et al., 2016; Nichols et al., 2018) and/or a marked loss of inhibition within injured regions of the brain (Li and Prince, 2002; Hunt et al., 2010; Pavlov et al., 2011; Almeida-Suhett et al., 2014, Almeida-Suhett et al., 2015; Butler et al., 2016; Nichols et al., 2018). However, it is unclear whether certain interneuron cohorts are preferentially lost after TBI as most studies focus on only a single cell type, and the effect of graded contusive injury has not been systematically evaluated.
Identifying how molecularly-distinct classes of interneurons are altered by mechanical injury is critical to understanding cortical network dysfunction in TBI and for designing precision therapies. Here, we took advantage of a widely used model of focal cortical contusion injury to directly compare and contrast the long-term effect of graded mechanical trauma on hippocampal interneuron subpopulations. We found a dramatic change in the diversity of hippocampal interneurons after contusive injury.
Section snippets
Animals
All experiments were first approved by the University of California, Irvine Animal Care and Use Committee and adhered to National Institutes of Health guidelines and regulations for the Care and Use of Laboratory Animals. Wild-type CD1 mice (Charles River, cat no. 022) were crossed with a hemizygous glutamic acid decarboxylase - enhanced green fluorescence protein (GAD67-GFP) knock-in line (Tamamaki et al., 2003). All animals were bred in house under a normal 12 h/12 h light/dark cycle and
Histological responses to graded CCI injury
We first examined gross damage to the brain 30 days following either 0.5 mm or 1.0 mm depth of impact at P60. Uninjured controls and sham-injured animals showed no overt cortical lesion in any animal examined (Fig. 1A). In all mice injured at 0.5 mm impact depth, the lesion consisted of a cortical cavity restricted to neocortex (n = 4 animals, Fig. 1B). In mice injured at 1.0 mm depth, the injury extended through the thickness of the neocortex and included substantial distortion of the
Discussion
Neuron loss is a major feature of TBI in both rodents and human (Baldwin et al., 1997; Anderson et al., 2005; Swartz et al., 2006; Hall et al., 2005a, Hall et al., 2005b, 2008; Buriticá et al., 2009), but the loss of interneurons following contusive injury has not been systematically evaluated. Our results provide the first comprehensive analysis of hippocampal interneurons following graded CCI injury. We found a dramatic reduction in interneuron density that was dependent on impact depth,
Acknowledgements
This work was supported by funding from the National Institutes of Health grants NINDS R00–NS085046, R01–NS096012 and T32–NS045540 and T32–NS082174. We thank Daniel Vogt and John Rubenstein for kindly sharing GAD67-GFP mice.
Author contributions
R.F.H. and J.C.F. designed research; J.C.F. and Y.J.K. performed experiments; R.F.H., and J.C.F. analyzed data; R.F.H. and J.C.F. wrote the manuscript; J.C.F. and Y.J.K. edited the manuscript.
References (50)
- et al.
GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury
Exp. Neurol.
(2015) - et al.
Regional distribution of fluoro-jade B staining in the hippocampus following traumatic brain injury
Exp. Neurol.
(2005) - et al.
Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice
Exp. Neurol.
(2016) - et al.
Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy
Brain Res.
(1989) - et al.
Posttraumatic epilepsy after controlled cortical impact injury in mice
Exp. Neurol.
(2009) - et al.
Posttraumatic mossy fiber sprouting is related to the degree of cortical damage in three mouse strains
Epilepsy Res.
(2012) - et al.
Motor cortex disinhibition in acute stroke
Clin. Neurophysiol.
(2000) - et al.
Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats
Neuroscience
(2011) - et al.
JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI
Exp. Neurol.
(2015) - et al.
Neuropsychiatric sequalae of traumatic brain injury
Psychosomatics
(2000)