Role of astrocytic TNF receptor 2 in synaptic stability and cognitive function after traumatic brain injury

Project: Research project

Project Details

Description

Project Summary Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. It is the result of direct or indirect mechanical impact to the brain causing disruption of its normal structure and function. Due to its heterogeneity (ranges from mild concussion to severe brain injury), progressive nature and the fact that multiple cell types and brain regions are affected at once, TBI causes a wide spectrum of long-lasting deficits for which identifying effective treatments has proven to be challenging. A prevalent feature of TBI is diffuse and progressive synaptic damage throughout the brain, leading to impairment of synaptic transmission and plasticity and, consequently, cognitive dysfunction, one of the most debilitating sequelae of TBI. Physiologic synaptic transmission relies upon bidirectional neuron-astrocyte communication, and astrocytic tumor necrosis factor (TNF) signaling is an important regulator of this process. To this end, preliminary studies in our laboratory have shown that astroglial TNFR2 is key to maintaining homeostatic neuron-astrocyte communication at the basis of physiologic synaptic function. In CNS disease, when astrocyte physiology, thus TNF signaling, are perturbed, neuron-astrocyte communication is disrupted and plasticity impaired, causing cognitive dysfunction. TNF is upregulated in TBI as well as other neurological diseases, where its soluble form solTNF, acting via TNFR1, has detrimental inflammatory functions, and its membrane-bound form tmTNF, acting via TNFR2, has protective/reparative roles. The NMDA co-agonist D-serine also plays a key role in physiologic synaptic transmission. Together with glutamate, neuronal D-serine sustains hippocampal synaptic processes at the basis of learning and memory functions. Our laboratory has shown that, following TBI, the source of D-serine switches from neurons to reactive astrocytes, and astroglial D-serine release leads to synaptic damage and cognitive impairment. Based on this evidence, our overarching hypothesis is that astroglial TNFR2 plays a protective role in counteracting synaptic dysfunction and related cognitive deficits in TBI. We also hypothesize that a TBI-induced unbalance in astroglial TNF signaling leads to pathological D-serine release from astrocytes, contributing to synaptic alterations in TBI. To investigate this hypothesis we propose two specific aims: Aim 1 will employ gain- and loss-of-function transgenic approaches to examine the role of astrocytic TNFR2 signaling in synaptic and cognitive function after CCI injury and whether astrocytic TNFR2 participates in the modulation of astroglial D- serine release; Aim 2 will use a pharmacological approach to examine whether targeting unbalanced TNF signaling in order to unmask protective TNFR2 activity after TBI will prevent astroglial D-serine release and counteract TBI-associated synaptic and cognitive dysfunction. Ultimately, our studies will advance the knowledge of the mechanisms underlying cognitive dysfunction in TBI and determine whether TNFR2 is a viable target for the development of treatments to limit cognitive decline and facilitate cognitive recovery in TBI, which is a major unmet need.
StatusActive
Effective start/end date9/15/209/14/22

Funding

  • National Institute of Neurological Disorders and Stroke: $422,125.00

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