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.

Keywords: dendritic spine; excitotoxicity; neurodegeneration; synaptic dysfunction; traumatic brain injury.

FIGURE 1

Timescale representation of the severity of damage following impact. Each time phase has the capacity to re-establish homeostasis through cellular repair or some form of treatment. If the cellular homeostasis is unresolved, however, the damage severity increases as time progresses. At the hyperacute time phase (minutes to hours) the damage severity is low, consisting of focal changes at the synaptic level such as hyperexcitability, increased membrane permeability (either through membrane disruption or receptor activity), and onset of excitotoxic conditions. During the acute phase (hours to several days), damage consists of further receptor alterations, activation of proteases and apoptotic pathways, mitochondrial dysfunction, and prolonged excitotoxic conditions. During the subacute phase (several days to weeks), regional deficits within the brain are observed due to cellular dysfunction, prolonged neuroinflammation, and onset of phosphorylated tau accumulation. During the chronic phase (months and beyond), major behavioral deficits and neuropsychiatric conditions are observed, including, but not limited to, impaired learning and memory, depression, and prolonged headaches. The neuropathology of chronic traumatic encephalopathy is also observed during this time (Guerriero et al., 2015; MacFarlane and Glenn, 2015). Created with BioRender.com.

FIGURE 2

Representation of the synapse within the hyperacute phase after impact. (1) Membrane permeability increases soon after impact through the influx/efflux of ions via voltage gated channels or rupturing of the pre-synaptic membrane. (2) The increase in Ca²⁺ primes glutamate filled vesicles and increases the rate of fusion and release of glutamate. (3) Increased and sustained release of glutamate (black dots) into the synaptic cleft activates NMDAr NR2B subunits (purple) and increases post-synaptic concentrations of Ca²⁺. This activates various kinases that phosphorylates AMPA GluR1 subunits (red), further promoting the influx of Ca²⁺. (4) Post-synaptic cytoskeleton alterations occur through phosphorylation (pink dots), with disinhibition of remodeling proteins, such as end-binding protein 3 (green), occurring to allow for the restructuring of the dendritic spine cytoskeleton. (5) Downstream cascades from the influx of Ca²⁺alter microtubule dynamics within the cytoskeleton of the neuron. Created with BioRender.com.

FIGURE 3

Representative image of main spine types that are commonly used in histological analysis described by Peters and Kaiserman-Abramof (1970). (A) Golgi-stained neuron showcasing the 4 main types of spines: thin (yellow), stubby (green), filopodia (red), and mushroom (purple). (B) Schematic representation of the types of spines to illustrate differences between shapes. Created with BioRender.com.

FIGURE 4

Representation of the biological timeline of the synapse after impact. (A) Thin synapse before an impact. Thin spines are considered a transitory spine phenotype, with the potential to transition in an excitatory synapse. (B) Within minutes after impact, synaptic changes within the hyperacute phase after impact. Membrane ruptures and ionic imbalances promote the hyperexcitability of the synapse, with an influx of Ca²⁺ into the post-synaptic terminal via NMDAr (purple). (C) Further damage to the synapse due to hyperexcitability and sustained release of glutamate from the pre-synaptic terminal is observed several hours after impact. Increased influx of Ca²⁺ into the post-synaptic terminal promotes the further upregulation of NMDAr, as well as upregulating GluR1 subunit of AMPAr (red). Disinhibition of synaptic reconstruction proteins, such as EB3 (green), occurs as restricting proteins become inactivated, promoting excitatory mushroom spine phenotype. Hyperexcitability promotes neurodegenerative pathways via overworked mitochondria and damage to the microtubule cytoskeleton of the neuron. Created with BioRender.com.