Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury

Abstract

Objectives: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. Design: Experimental animal study. Setting: Research laboratory. Subjects: Adult male mice and hippocampal brain slices. Interventions: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). Measurements and Main Results: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. Conclusions: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury–induced persistent cognitive deficits.

Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits

“…33,34 Ono-160 was described in a most recent patent (WO 2015/115673 A1), and L-655,708 has been widely investigated in preclinical studies. 6,23,24,35 Primary hippocampal neuronal culture…”

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice

“…The trials that involved the introduction of a new task (specifically trials 1, 2, 5, and 8) were used to assess problem-solving ability. 13,23 Trial 1 was the “door open” task, during which both the door and underpass were open. In trial 2, the “underpass” task was introduced, whereby the door was closed, and only the underpass remained open.…”

“…For the behavioral studies, we selected a sample size of 20 to 24 animals per group, based on previous experience with the puzzle box assay. 13,23 A post hoc analysis revealed that this sample size provided 90% power to detect a treatment effect size of f = 0.41.…”

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

“…It has been shown that hippocampus dysfunction is associated with cognitive deficits following a TBI [6,8,9]. Existing treatments for TBI primarily focus on immediate neurosurgical procedures and long-term behavioral rehabilitation, but few treatments are sufficient to improve TBIinduced cognitive deficits [10,11]. TBI differs from other diseases in that it involves different periods after the injury.…”