Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability in people younger than 45 and is a significant public health concern. In addition to primary mechanical damage to cells and tissue, TBI involves additional molecular mechanisms of injury, termed secondary injury, that continue to evolve over hours, days, weeks, and beyond. The trajectory of recovery after TBI is highly unpredictable and in many cases results in chronic cognitive and behavioral changes. Acutely after TBI, there is an unregulated release of glutamate that cannot be buffered or cleared effectively, resulting in damaging levels of glutamate in the extracellular space. This initial loss of glutamate homeostasis may initiate additional changes in glutamate regulation. The excitatory amino acid transporters (EAATs) are expressed on both neurons and glia and are the principal mechanism for maintaining extracellular glutamate levels. Diffusion of glutamate outside the synapse due to impaired uptake may lead to increased extrasynaptic glutamate signaling, secondary injury through activation of cell death pathways, and loss of fidelity and specificity of synaptic transmission. Coordination of glutamate release and uptake is critical to regulating synaptic strength, long-term potentiation and depression, and cognitive processes. In this review, we will discuss dysregulation of extracellular glutamate and glutamate uptake in the acute stage of TBI and how failure to resolve acute disruptions in glutamate homeostatic mechanisms may play a causal role in chronic cognitive symptoms after TBI.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…The recycled glutamate serves as the principle source of synaptically released glutamate for neurotransmission. In addition to providing a mechanism of efficiently recycling extracellular glutamate, the 'astrocytic cradle' creates an anatomical and functional barrier that blocks the 'spillover' of glutamate into the extrasynaptic space (Dorsett et al, 2016;McCullumsmith and Sanacora, 2015). Although glutamate binds to EAATs with high affinity, not all the bound glutamate is immediately transported across the plasma membrane of astrocytes (Dorsett et al, 2016).…”

“…In addition to providing a mechanism of efficiently recycling extracellular glutamate, the 'astrocytic cradle' creates an anatomical and functional barrier that blocks the 'spillover' of glutamate into the extrasynaptic space (Dorsett et al, 2016;McCullumsmith and Sanacora, 2015). Although glutamate binds to EAATs with high affinity, not all the bound glutamate is immediately transported across the plasma membrane of astrocytes (Dorsett et al, 2016). EAAT-bound glutamate may become 'unbound', released, and rebound to neighboring glutamate transporters, thus bouncing from one transporter to the other until it is eventually transported across the plasma membrane (Tzingounis and Wadiche, 2007).…”

“…EAAT-bound glutamate may become 'unbound', released, and rebound to neighboring glutamate transporters, thus bouncing from one transporter to the other until it is eventually transported across the plasma membrane (Tzingounis and Wadiche, 2007). This process of the temporary holding of glutamate before transport is referred to as 'buffering' and it helps limit its spillover outside the cradle (Dorsett et al, 2016). Finally, through their podocytic endfeet, astrocytes come in close proximity to blood vessels and vascular pericytes, leaving an empty space-a 'no man's land' of extracellular space that forms an integral part of the blood-brain barrier (BBB) and brain lymphatic systems (Iliff and Nedergaard, 2013;Louveau et al, 2015).…”

“…The extent and effects of glutamate diffusion will depend upon the spatial arrangement of extrasynaptic glutamate receptors, glutamate synapses, and their glutamate transporter buffering zones (Dorsett et al, 2016;McCullumsmith and Sanacora, 2015;Tzingounis and Wadiche, 2007). In physiological conditions, the buffering and release of glutamate is tightly regulated by EAATs and glutamate is not allowed to diffuse beyond 0.5 μm from its point of origin, thus restricting access to extrasynaptic glutamate receptors (Tzingounis and Wadiche, 2007).…”

“…Extracellular diffusion of glutamate can lead to the loss of synaptic fidelity, decreased specificity of neurotransmission, and lead to 'noisy', non-specific, and disruptive neural activity experienced by patients as cognitive and affective symptoms (Dorsett et al, 2016). Although precise data are lacking, we speculate that inflammatory activation in mood disorders might lead to increased AMPA activity during early phases followed by desensitization and decreased AMPA activity in later stages resulting in synaptic depression, decreased transmission efficiency, and impaired synaptic plasticity (Choquet and Triller, 2013;Popoli et al, 2012;Pribiag and Stellwagen, 2014;Pribiag and Stellwagen, 2013).…”