Elsevier

Neurobiology of Disease

Volume 129, September 2019, Pages 208-216
Neurobiology of Disease

Original research article
Selective vulnerability of hippocampal interneurons to graded traumatic brain injury

https://doi.org/10.1016/j.nbd.2018.07.022Get rights and content

Highlights

  • Interneuron density after focal contusion injury is dependent on impact depth, hippocampal sub-region and laminar position.

  • There is no interneuron loss in hippocampus contralateral to the injury.

  • Interneurons in principal cell and polymorph layers are more vulnerable to injury than cell types in the molecular layer

Abstract

Traumatic brain injury is a major risk factor for many long-term mental health problems. Although underlying mechanisms likely involve compromised inhibition, little is known about how individual subpopulations of interneurons are affected by neurotrauma. Here we report long-term loss of hippocampal interneurons following controlled cortical impact (CCI) injury in young-adult mice, a model of focal cortical contusion injury in humans. Brain injured mice displayed subfield and cell-type specific decreases in interneurons 30 days after impact depths of 0.5 mm and 1.0 mm, and increasing the depth of impact led to greater cell loss. In general, we found a preferential reduction of interneuron cohorts located in principal cell and polymorph layers, while cell types positioned in the molecular layer appeared well preserved. Our results suggest a dramatic shift of interneuron diversity following contusion injury that may contribute to the pathophysiology of 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.

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