Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

Abstract

The clinical manifestations that occur after traumatic brain injury (TBI) include a wide range of cognitive, emotional, and behavioral deficits. The loss of excitatory synapses could potentially explain why such diverse symptoms occur after TBI, and a recent preclinical study has demonstrated a loss of dendritic spines, the postsynaptic site of the excitatory synapse, after fluid percussion injury. The objective of this study was to determine if controlled cortical impact (CCI) also resulted in dendritic spine retraction and to probe the underlying mechanisms of this spine loss. We used a unilateral CCI and visualized neurons and dendtritic spines at 24 h post-injury using Golgi stain. We found that TBI caused a 32% reduction of dendritic spines in layer II/III of the ipsilateral cortex and a 20% reduction in the dendritic spines of the ipsilateral dentate gyrus. Spine loss was not restricted to the ipsilateral hemisphere, however, with similar reductions in spine numbers recorded in the contralateral cortex (25% reduction) and hippocampus (23% reduction). Amyloid-b (Ab), a neurotoxic peptide commonly associated with Alzheimer disease, accumulates rapidly after TBI and is also known to cause synaptic loss. To determine if Ab contributes to spine loss after brain injury, we administered a c-secretase inhibitor LY450139 after TBI. We found that while LY450139 administration could attenuate the TBI-induced increase in Ab, it had no effect on dendritic spine loss after TBI. We conclude that the acute, global loss of dendritic spines after TBI is independent of c-secretase activity or TBI-induced Ab accumulation.

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

“…29 In the present study, we focused our spine counts on layers II/III of the cortex and report that a single mTBI causes a 13% loss of spines in the AO dendrites in young male mice, with a greater spine loss occurring after mTBI on the same dendrites in aged male mice. Combined together, these studies of dendritic spines after TBI show that this is a common phenomenon that occurs in a severe TBI model (controlled cortical impact), 18,30 a moderate TBI model (FPI), 28 and our mild TBI model. Thus, our work and that of others demonstrate that the loss of dendritic spines is an event that occurs after all severities of TBI and may be one of the common acute events that occur after head trauma, even in the absence of neuronal cell death, axonal injury, or inflammation.…”

“…18 Bright-field microscopy images of pyramidal neurons in layers II/III of the cortex were captured, and the number of dendritic spines on basal shaft (BS) and apical oblique (AO) dendrites was quantified. BS dendrites project directly off the cell soma, and our counts incorporated dendritic spines along a 20-mm section of the shaft between 30 and 100 mm away from the soma.…”

“…We have recently demonstrated that a global decrease in dendritic spine number occurs in mice after a controlled cortical impact injury, 18 with a 27% loss of dendritic spines occurring in layer II/III of the ipsilateral cortex, and spine loss in sites far distant from the impact zone, such as the contralateral entorhinal cortex. 18 Dendritic Figure 8 Repeat mild traumatic brain injury (rmTBI) does not alter tau phosphorylation in the cortex of 3xTg mice. 3xTg mice were exposed to 5 mTBIs per week for 4 weeks (20 mTBIs total) and euthanized at 24 hours or 1 month after injury.…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Indeed, in the last few decades, multiple lines of evidence have shown that disruptions in dendritic spine shape, size, or number invariably accompany various brains disorders, such as schizophrenia [6][7][8][9], Angelman syndrome [10], and Rett syndrome [11][12][13], and may be even be a characteristic feature of traumatic brain injuries [14,15]. What do these various neuropsychiatric and neurodevelopmental diseases share in common?…”

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

“…Blast-injury, among other forms of experimental TBI, causes mild forms of brain damage and diffuse axonal injury. A recent study has shown that controlled cortical impact injury causes local as well as widespread cortical neuronal dendrite degeneration and loss [75]. The mechanisms underlying such events are not well understood, but may, at least in part, result from intracellular transcriptional modulation due to epigenetic changes induced by injury.…”