Glutamate and GABA imbalance following traumatic brain injury

Abstract

Traumatic brain injury (TBI) leads to multiple short- and long-term changes in neuronal circuits that ultimately conclude with an imbalance of cortical excitation and inhibition. Changes in neurotransmitter concentrations, receptor populations, and specific cell survival are important contributing factors. Many of these changes occur gradually, which may explain the vulnerability of the brain to multiple mild impacts, alterations in neuroplasticity, and delays in the presentation of posttraumatic epilepsy. In this review, we provide an overview of normal glutamate and GABA homeostasis and describe acute, subacute, and chronic changes that follow injury. We conclude by highlighting opportunities for therapeutic interventions in this paradigm.

Figure. Summary of Glutamate and GABA homeostasis and changes following traumatic brain injury

The figure illustrates a schematic relationship of a glutamatergic synapse between pyramidal neurons (green neurons), an astrocyte (bottom right), and an inhibitory GABAergic synapse between an interneuron (blue neuron in the top right) and, in this case the cell body of the pyramidal cell. Panel A. Baseline homeostatic relationship of glutamate and GABA begins with (1) a depolarizing current traveling down a pyramidal cell. (2) This is followed by Ca⁺⁺ mediated release of glutamate from the presynaptic neuron and action on local AMPA and NMDA receptors. (3) Na⁺ enters the cell triggering depolarization, (4) followed by Ca⁺⁺ via NMDA receptors. (5) There is subsequently immediate early gene (IEG) activation. (6) Glutamate is taken up by the GLT-1/EAAT transporter on nearby astrocytes. (7) Glutamate is converted to glutamine by glutamine synthase (GS) and shuttled back to the presynaptic cell and nearby interneurons for conversion to GABA via glutaminase (GLS) and then glutamate decarboxylase (GAD). (8) GABA is released from local interneurons and acts on GABA-A and GABA-B receptors and is taken back up by GAT-1. (9) Cl⁻ and K⁺ enter the presynaptic pyramidal cell restoring the cell membrane to its resting state. Panel B. Acutely following TBI there is (1) rapid depolarization of the pyramidal cell and increased Ca⁺⁺ entry into the presynaptic cell prompting (2) increased glutamate release into the synaptic cleft. Glutamate then acts on AMPA and NMDA receptors, as there are local changes that attempt to compensate for the increased glutamate, e.g. downregulation of NMDA subunits. (3) Na+ enters the cell triggering depolarization, (4) followed by increased Ca⁺⁺ via NMDA receptors and (5) increased IEG activation. (6) Less glutamate is removed from the synapse given decreased expression of GLT-1/EAAT transporter on astrocytes. (7) Glutamate that is taken up is rapidly converted to glutamine and recycled. (8) GABA is released from local interneurons, however (9) changes in GABA-A subunit expression lead to changes in the phasic inhibition of the presynaptic pyramidal cell and deficits in membrane repolarization. Panel C. Chronically following TBI there is (1) depolarization of the pyramidal cell and (2) glutamate release into the synaptic cleft, which acts on AMPA and NMDA receptors, now with different expression of receptor subunits, e.g. NR2A shifts to NR2B. (3) Na⁺ enters the cell triggering depolarization, (4) followed by Ca⁺⁺ via NMDA receptors and (5) IEG activation. (6) Glutamate is taken up by the GLT-1/EAAT transporter on nearby astrocytes and (7) converted to glutamine. (8) There is GABA interneuron cell death and (9) persistent GABA-A receptor dysfunction that leads to (10) less hyperpolarization and a hyperexcitable state of the presynaptic cell. Abbreviations: Glu = glutamate, gln = glycine, Cl− = chloride, K+ = potassium, Na+ = sodium, Ca++ = calcium, IEG = immediate early gene, NR2B = NMDA receptor subunit 2B, GLT/EAAT = glutamate transporter, excitatory amino acid transporter, GS = glutamine synthase, GLS = glutaminase, GAD = glutamate decarboxylase. GAT-1 = GABA transporter.