Diminished Dentate Gyrus Filtering of Cortical Input Leads to Enhanced Area Ca3 Excitability after Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) disrupts hippocampal function and can lead to long-lasting episodic memory impairments. The encoding of episodic memories relies on spatial information processing within the hippocampus. As the primary entry point for spatial information into the hippocampus, the dentate gyrus is thought to function as a physiological gate, or filter, of afferent excitation before reaching downstream area Cornu Ammonis (CA3). Although injury has previously been shown to alter dentate gyrus network excitability, it is unknown whether mTBI affects dentate gyrus output to area CA3. In this study, we assessed hippocampal function, specifically the interaction between the dentate gyrus and CA3, using behavioral and electrophysiological techniques in ex vivo brain slices 1 week following mild lateral fluid percussion injury (LFPI). Behaviorally, LFPI mice were found to be impaired in an object-place recognition task, indicating that spatial information processing in the hippocampus is disrupted. Extracellular recordings and voltage-sensitive dye imaging demonstrated that perforant path activation leads to the aberrant spread of excitation from the dentate gyrus into area CA3 along the mossy fiber pathway. These results suggest that after mTBI, the dentate gyrus has a diminished capacity to regulate cortical input into the hippocampus, leading to increased CA3 network excitability. The loss of the dentate filtering efficacy reveals a potential mechanism by which hippocampal-dependent spatial information processing is disrupted, and may contribute to memory dysfunction after mTBI.

Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward

“…Due to the nature of FPI models requiring an opening in the skull, translation of mechanisms and interventions to human head injury is often difficult because the majority of human head injuries involve closed head injury mechanisms ( O’Connor et al, 2011 ). FPI model of TBI have been primarily studied in animals, such as the cat ( Stalhammar et al, 1987 ), sheep ( Millen et al, 1985 ), swine ( Fritz et al, 2005 ), mice ( Carbonell et al, 1998 ; Folweiler et al, 2018 ; Ogino et al, 2018 ), and rat ( Gorse and Lafrenaye, 2018 ; Katz and Molina, 2018 ; McIntosh et al, 1987 ). Many of these studies typically represent the adult brain, however those employing rats ( Prins and Hovda, 2003 ) and piglets ( Fritz et al, 2005 ; Lafrenaye et al, 2015 ) have been used to model the newborn and juvenile brain.…”

Traumatic Brain Injury Diminishes Feedforward Activation of Parvalbumin-Expressing Interneurons in the Dentate Gyrus

“…Granule cells no longer sparsely fire APs, and evoked extracellular burst discharges are increased in the granule cell layer in vivo ( Lowenstein et al, 1992 ). This shift toward a hyperexcitable network state leads to a break down in the physiological filtering function of the DG and is associated with spatial memory impairments ( Folweiler et al, 2018 ).…”

Current ex vivo and in vitro approaches to uncovering mechanisms of neurological dysfunction after traumatic brain injury

“…In vivo injuries have been modeled in rodents and provide a close approximation to the human condition. Using ex vivo brain slice analysis of in vivo injuries (as shown in Figure 1A), recent studies have shown changes in circuit excitability (11)(12)(13)(14)(15), neuro-immune interactions (16) and cell-specific changes (17,18). Our recent slice physiology studies after FPI identified a role for the innate immune receptor, toll-like receptor 4 (TLR4), in enhancing calcium-permeable AMPA receptor currents early after FPI.…”

“…Swine have been utilized to simulate human rotational injury biomechanics and have addressed circuit-level questions using slices (21,22). Across species, ex vivo analyses enable the use of cutting-edge techniques such as voltage sensitive dyes (11,23), glutamate uncaging (24), and optogenetic stimulation (25). In particular, use of voltage sensitive dye imaging in acute slices enabled Folweiler and colleagues to visualize the spatial and temporal spread of focally evoked activity in the hippocampus and investigate how this activity was altered following trauma (11)*.…”