Rapid Changes in Synaptic Strength After Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) affects millions of Americans annually, but effective treatments remain inadequate due to our poor understanding of how injury impacts neural function. Data are particularly limited for mild, closed-skull TBI, which forms the majority of human cases, and for acute injury phases, when trauma effects and compensatory responses appear highly dynamic. Here we use a mouse model of mild TBI to characterize injury-induced synaptic dysfunction, and examine its progression over the hours to days after trauma. Mild injury consistently caused both locomotor deficits and localized neuroinflammation in piriform and entorhinal cortices, along with reduced olfactory discrimination ability. Using whole-cell recordings to characterize synaptic input onto piriform pyramidal neurons, we found moderate effects on excitatory or inhibitory synaptic function at 48 h after TBI and robust increase in excitatory inputs in slices prepared 1 h after injury. Excitatory increases predominated over inhibitory effects, suggesting that loss of excitatory-inhibitory balance is a common feature of both mild and severe TBI. Our data indicate that mild injury drives rapidly evolving alterations in neural function in the hours following injury, highlighting the need to better characterize the interplay between the primary trauma responses and compensatory effects during this early time period.

Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes

“…5 A). Since TBI is known to lead to an imbalance in cortical excitation and inhibition [ 7 , 11 , 15 , 19 , 110 ] we predicted that the changes in synapse number suggested by the reduction in synaptophysin levels might be due to changes in the levels and ratios of excitatory glutamatergic and inhibitory GABAergic synapses. To investigate this possibility we evaluated the levels of PSD95, a marker of glutamatergic terminals [ 24 ], and of Gephyrin, a marker of GABAergic terminals [ 91 ] in the PFC of sham and injured mice.…”

“…In particular, these data suggest that after rmTBI there is a temporary preferential loss of inhibitory synapses and a more robust regeneration of excitatory synapses, resulting in a temporary increase in the ratio of excitatory:inhibitory activity. A change in the balance of cortical excitatory and inhibitory activity after injury has been described by others [ 19 ] with many showing a specific loss of inhibitory synaptic activity [ 7 , 11 , 15 , 110 ]. The PSD95 and Gephyrin levels return to baseline by 1 w after rmTBI and might thereby restore the balance of excitatory and inhibitory synaptic activity.…”

“…In support of this prediction, synaptophysin levels decreased acutely after rmTBI and this change was still apparent at 20 w post-injury. The acute elevation in PSD95 levels and reduction in Gephyrin levels may be taken to indicate alterations in the ratio of excitatory and inhibitory synapses as has also been suggested to occur after TBI [ 7 , 11 , 15 , 19 , 110 ]. We cannot rule out that these changes in synaptophysin, PSD95 and Gephyrin levels are due to changes in protein expression levels and not in synapse number however, others have shown that nerve terminals can be quantified by the levels of these nerve terminal markers [ 108 ], and these results certainly suggest an injury-induced increase in synaptic plasticity and remodeling.…”

Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer’s-like Pathology in the Hippocampus by Altering the Phenotype of Microglia in APP/PS1 Mouse Model

“…There is also evidence showed that TBI could also affects the synaptic plasticity 37 . Synaptic function is rapidly disturbed after TBI 38 , and could also continue to the chronic stage 39 . Our experiment evaluates the synaptic function in the cortex and in the hippocampus of each group of mice.…”

Current ex vivo and in vitro approaches to uncovering mechanisms of neurological dysfunction after traumatic brain injury

“…In vivo injuries have been modeled in rodents and provide a close approximation to the human condition. Using ex vivo brain slice analysis of in vivo injuries (as shown in Figure 1A), recent studies have shown changes in circuit excitability (11)(12)(13)(14)(15), neuro-immune interactions (16) and cell-specific changes (17,18). Our recent slice physiology studies after FPI identified a role for the innate immune receptor, toll-like receptor 4 (TLR4), in enhancing calcium-permeable AMPA receptor currents early after FPI.…”