Friday, April 19, 2024
4/19/2024
Project Summary/Abstract Traumatic brain injury (TBI) is a major cause of mortality in both military and civilian populations. Meanwhile, TBI survivors are at greater risk for long-term increases in brain network hyper-excitability. Despite the global burden of TBI, there have been very few animal studies focused on mechanisms of excitability at synaptic and network levels. Our goal is to dissect the potential mechanisms underlying TBI-associated excitability after mild and severe brain injury. Recently, we observed an increased incidence of noncanonical glutamate release events, known as glutamatergic plumes, 48 hours after TBI. Increased frequency of plumes can facilitate spreading depolarization (SD) initiation. SD is an excitable phenomenon detected after TBI and is correlated with increased tissue damage and poor outcome. Thus, the prevalence of plumes suggests that the network is dysfunctional after TBI. We will examine this novel form of aberrant glutamate signaling in the brain, including the consequences of plumes on post-TBI excitability. We will employ simultaneous in vivo whole-cell recording and two-photon microscopy, alongside genetic tools to manipulate mechanisms of plumes. We will examine both male and female mice as females experience worse excitability-related complications post-TBI. In Aim 1, we will determine the source of plumes in controlled cortical impact (CCI) and mild TBI models, and how those mechanisms are altered in female mice. Based on our recent data, glutamate reuptake failure by astrocytes facilitates plumes. Thus, we hypothesize that astrocytic clearance mechanisms are responsible for glutamate plumes after TBI. To test this hypothesis, we will genetically ablate/enhance key astrocyte mediators of glutamate clearance in vivo. These experiments will establish a precise mechanism of glutamate dysfunction (plumes) in the post-TBI environment. In Aim 2, we will determine whether plumes can influence synaptic plasticity and network dynamics after TBI. Our pilot data shows calcium loading is enhanced during spontaneous neuronal activity after TBI. Based on current literature, glutamate dysfunction, such as increases in extracellular glutamate, can drive calcium influx in the naïve brain. Since elevation in intracellular calcium is an important feature of long-term potentiation (LTP) induction, we hypothesize that plumes in TBI drive brief but strong postsynaptic calcium elevations contributing to LTP and thus to an increase in network excitability. This is important since aberrant changes in synaptic plasticity are implicated in many neurological disorders. Notably, we will ask if and how plumes induce plasticity in dendrites by performing two-photon imaging of dendritic calcium transients after TBI. Furthermore, we will examine the mechanistic connection between plumes (and astrocytic mechanisms) and SD-associated calcium load after TBI. We hypothesize that plumes provide the stimulus necessary for the activation of NMDA receptors, thereby causing calcium to surge during SD after TBI. Thus, plumes may enhance the damage caused by both SD and neuronal calcium elevation after TBI. Our findings will result in novel and targeted mechanisms of post-traumatic excitability, including potential drug targets.
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