Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

Joshua A Beitchman; Daniel R Griffiths; Yerin Hur; Sarah B Ogle; Caitlin E Bromberg; Helena W Morrison; Jonathan Lifshitz; P David Adelson; Theresa Currier Thomas

doi:10.3389/fnins.2019.01434

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

Front Neurosci. 2020 Jan 21:13:1434. doi: 10.3389/fnins.2019.01434. eCollection 2019.

Authors

Joshua A Beitchman^{1

2

3}, Daniel R Griffiths^{1

2}, Yerin Hur^{1

2}, Sarah B Ogle^{1

2

4}, Caitlin E Bromberg^{1

2}, Helena W Morrison⁵, Jonathan Lifshitz^{1

2

6}, P David Adelson^{1

2}, Theresa Currier Thomas^{1

2

6}

Affiliations

¹ Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States.
² Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.
³ College of Graduate Studies, Midwestern University, Glendale, AZ, United States.
⁴ Banner University Medical Center, Phoenix, AZ, United States.
⁵ College of Nursing, University of Arizona, Tucson, AZ, United States.
⁶ Phoenix VA Health Care System, Phoenix, AZ, United States.

Abstract

Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting and late-onset anxiety disorders indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that the development of TBI-induced anxiety-like behavior in an experimental model of TBI is mediated by changes in glutamate neurotransmission within the amygdala. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. The expression of anxiety-like behavior at 28 DPI coincided with decreased evoked glutamate release and slower glutamate clearance in the CeA, not BLA. Numerous factors contribute to the changes in glutamate neurotransmission over time. In two additional animal cohorts, protein levels of glutamatergic transporters (Glt-1 and GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28 DPI. Astrocytosis and microglial activation have been shown to drive maladaptive glutamate signaling and were histologically assessed over 28 DPI. Alterations in glutamate neurotransmission could not be explained by changes in protein levels for glutamate transporters, mGluR2 receptors, astrocytosis, and microglial activation. Presynaptic modulators, BDNF and TrkB, were significantly decreased at 28 DPI in the amygdala. Dysfunction in presynaptic regulation of glutamate neurotransmission may contribute to anxiety-related behavior and serve as a therapeutic target to improve circuit function.

Keywords: amperometry; amygdala; chronic; diffuse traumatic brain injury; glutamate neurotransmission.

Grants and funding

R01 NS100793/NS/NINDS NIH HHS/United States