Hyperacute Excitotoxic Mechanisms and Synaptic Dysfunction Involved in Traumatic Brain Injury

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.

Comprehensive RNA Expression Analysis Revealed Biological Functions of Key Gene Sets and Identified Disease-Associated Cell Types Involved in Rat Traumatic Brain Injury

“…TBI can be divided into four phases: hyperacute (minutes to hours), acute (hours to several days), subacute (several days to weeks), and chronic (months and beyond) [ 56 ]. Our results showed that during the hyperacute phase (30 min to 12 h postinjury), the cellular activity of microglia in the injury group was significantly lower than in the sham group, while in the acute phase (1 day to 3 days postinjury) the difference was not significant.…”

Multi-mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

“…The processes underlying TBI-induced excitotoxicity begin within seconds of the initial trauma, with dysfunction of the cell membrane and ion channels leading to increased intracellular calcium ([Ca 2+ ]i) [25]. This increase in [Ca 2+ ]i triggers release of vesicles containing neurotransmitters including glutamate into the synaptic cleft as early as 30 minutes following TBI [25]. Excess glutamate stimulates NMDA and AMPA receptors on nearby neurons, triggering depolarization and increased [Ca 2+ ]i that propagates a wave of excess excitation [26].…”

“…Excess glutamate stimulates NMDA and AMPA receptors on nearby neurons, triggering depolarization and increased [Ca 2+ ]i that propagates a wave of excess excitation [26]. While this excitation is initially tolerable to neurons, mitochondrial failure begins to occur within four hours of trauma, leading to energy depletion, neuronal apoptosis and neurodegeneration [25]. These alterations in [Ca 2+ ]i have been observed to persist up to seven days after TBI, in association with neuronal dysfunction [27].…”

Mathematical model of mechanobiology of acute and repeated synaptic injury and systemic biomarker kinetics

“…Reported mathematical models of brain-scale blast-induced biomechanics can predict local brain tissue stress-strain profiles ( Gupta et al, 2017 ). However, in spite of large volume of work on mathematical modeling of synaptic, axonal and neuronal neurotransmission, metabolism and signaling pathways very little has been reported on modeling synaptic mechanobiology ( Przekwas et al, 2016 ; Hall et al, 2021 ; Keating and Cullen, 2021 ; Hoffe and Holahan, 2022 ; Procès et al, 2022 ). In the present paper we introduce an initial formulation of a computational model of a mechanobiological “response” of a neuronal synapse to acute and repeated sub-concussive blast loads.…”