Abstract
The biological response of brain tissue to biomechanical strain are of fundamental importance in understanding sequela of a brain injury. The time after impact can be broken into four main phases: hyperacute, acute, subacute and chronic. It is crucial to understand the hyperacute neural outcomes from the biomechanical responses that produce traumatic brain injury (TBI) as these often result in the brain becoming sensitized and vulnerable to subsequent TBIs. While the precise physical mechanisms responsible for TBI are still a matter of debate, strain-induced shearing and stretching of neural elements are considered a primary factor in pathology; however, the injury-strain thresholds as well as the earliest onset of identifiable pathologies remain unclear. Dendritic spines are sites along the dendrite where the communication between neurons occurs. These spines are dynamic in their morphology, constantly changing between stubby, thin, filopodia and mushroom depending on the environment and signaling that takes place. Dendritic spines have been shown to react to the excitotoxic conditions that take place after an impact has occurred, with a shift to the excitatory, mushroom phenotype. Glutamate released into the synaptic cleft binds to NMDA and AMPA receptors leading to increased Ca2+ entry resulting in an excitotoxic cascade. If not properly cleared, elevated levels of glutamate within the synaptic cleft will have detrimental consequences on cellular signaling and survival of the pre- and post-synaptic elements. This review will focus on the synaptic changes during the hyperacute phase that occur after a TBI. With repetitive head trauma being linked to devastating medium – and long-term maladaptive neurobehavioral outcomes, including chronic traumatic encephalopathy (CTE), understanding the hyperacute cellular mechanisms can help understand the course of the pathology and the development of effective therapeutics.
Highlights
The synapse is regarded as the fundamental site of communication between cells of the nervous system and synaptic dysfunction may represent a choke point for the multitude of upstream factors and downstream responses that lead to neuron atrophy or death
Neuroinflammation plays a significant role in modulating the damage after brain injuries, with the activation of numerous proinflammatory cytokines such as interleukin-1, 6, tumor necrosis factor-α (TNF- α), and interferon-γ reported within the hyperacute phase following injury (Patterson and Holahan, 2012; Smith et al, 2012; Xiong et al, 2018)
This has been observed in animal models of traumatic brain injury (TBI), with increased calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and GluR1 observed within the hippocampus as early as 15 min after using weighted drop controlled cortical impact (CCI; Schumann et al, 2008) and 1 h post fluid percussion injury (FPI) (Atkins et al, 2006)
Summary
The synapse is regarded as the fundamental site of communication between cells of the nervous system and synaptic dysfunction may represent a choke point for the multitude of upstream factors and downstream responses that lead to neuron atrophy or death. Given that TBI can be regarded as a singular event (Wojnarowicz et al, 2017), the cellular processes that take place at the synapse dictate how the cell responds to the change in environment These cellular processes can be categorized into four main time phases: hyperacute, acute, subacute, and chronic (Guerriero et al, 2015; MacFarlane and Glenn, 2015). While much research exists on the changes occurring days to months after TBI, there is comparatively little research investigating the hyperacute synaptic changes occurring within minutes to hours These short-term changes could reveal the pathological mechanisms that are responsible for the later stages of neurodegeneration which may help shed light on potential therapeutic routes for neurodegenerative diseases associated with head trauma. This review will focus on and highlight the synaptic dysfunction during the hyperacute phase post-TBI, combining crucial findings from both in vitro and in vivo data to better understand what occurs at the synapse within minutes to hours after an impact has occurred
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