Browsing by Subject "NMDA receptor"

Now showing 1 - 3 of 3
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    A Computational Study of Cortical Spreading Depression
    (2016-05) O'Connell, Rosemary
    Spreading depression (SD) is a pathological phenomenon of the central nervous system in which normal cellular function is disrupted by a prolonged depolarization, which spreads spatially at a rate of several millimeters per minute. SD is connected to a number of medical conditions, including migraine with aura, traumatic brain injury, and epilepsy. This thesis presents a general framework for modeling spreading depression as a multiphasic continuum that is based on fully incorporating biophysical principles, including electrodiffusion and osmosis. The generality of the model allows us to explore how many different aspects of the physiology may impact the system, which we do through four specific models. In particular, we explore the effects of fluid flow within the extracellular space, adding a glial compartment, and including two neuronal compartments in one spatial dimension. In addition, we explore features of SD propagation in two spatial dimensions. In each of these four specific models, we vary several different parameters to understand the role they have in the initiation and propagation of SD. We find that many aspects of the system affect the speed of propagation and that glial cells play a significant role in the extracellular potential variation seen during SD. Additionally, some parameters affect the relative timing of the various changes that take place during SD.
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    The GLUN2B subunit of the NMDA receptor as an effector of inhibitory and pro-nociceptive neuromodulators
    (2024-11) Xie, Tongzhen
    Chronic pain affects over 20% of adults in the U.S., imposing a significant personal and economic burden, while most existing therapies are not suitable for long-term use. Chronic pain patients critically need an alternative effective treatment with minimal side effects. To create such treatments, it is essential to understand the pain circuitry and different mechanisms of how chronic pain can develop. One promising therapeutic target is the GluN2B-containing NMDA receptor in the spinal cord dorsal horn. Antagonizing this receptor has been shown to prevent the development of central sensitization, a key driver of chronic pain. Building on the understanding of NMDA receptors, this thesis described both pronociceptive and inhibitory modulation of spinal GluN2B-NMDA receptors using a novel NMDA-evoked calcium response assay in the mouse spinal cord dorsal horn. The results showed that the spinal NMDA receptor mediates the maladaptive involvement of the VGF-derived peptide TLQP-62. In contrast, the inhibitory effects of agmatine on spinal NMDA receptor activity require intact spinal PSD95-nNOS tethering. While further research is required to fully characterize the direct interactions of these modulators with NMDA receptors, it is hoped that this study will help the goal of developing safe and effective therapeutics for pain patients.
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    The mechanism of HIV-1 Tat-induced changes in NMDA receptor function
    (2014-08) Krogh, Kelly A.
    Worldwide, more than 35 million people are currently infected with the human immunodeficiency virus (HIV). Approximately half of HIV-infected patients in the U.S. experience cognitive impairment despite effective control of viral load with combination anti-retroviral therapy (cART). The neurological complications that stem from an HIV infection are known as HIV-associated neurocognitive disorders (HAND). HAND ranges in severity from subtle difficulties with day-to-day tasks to severe functional impairment requiring assistance to survive. Although cART has improved patient survival by effectively managing viral load, it is ineffective at treating the majority of HAND. Consequently, the prevalence of HAND remains persistently high. The symptoms of HAND correlate with neuronal damage, such as synapse loss and dendritic beading. Such synaptodendritic damage results from HIV-infected cells within the central nervous system (CNS) shedding neurotoxic agents, such as the HIV-1 protein transactivator of transcription (Tat). Tat potentiates N-methyl D-aspartate (NMDA) receptor function allowing excessive Ca2+ influx leading to neurotoxicity. In this dissertation, two studies are outlined investigating the mechanisms of NMDA receptor (NMDAR) dysfunction following exposure to Tat. The graphical abstract summarizes these studies. First, the effect of Tat on NMDAR function was investigated. This study showed that Tat caused a time-dependent, biphasic change in NMDAR function. Initially, Tat potentiated NMDAR function via the low-density lipoprotein receptor-related protein (LRP) and activation of Src tyrosine kinase. Subsequently, NMDAR function adapted by gradually returning to basal levels following 24 h exposure to Tat and eventually falling below control responses by 48 h. Adaptation resulted from activation of a nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), cGMP-dependent protein kinase (PKG) signaling pathway. Next, effectors downstream of PKG responsible for adaptation of NMDAR function were identified. Tat activated a signaling pathway including the small GTPase RhoA and Rho-associated protein kinase (ROCK). RhoA/ROCK activation caused remodeling of the actin cytoskeleton resulting in reduced NMDAR function. Taken together, these studies indicate that Tat causes a biphasic change in NMDAR function. Potentiation of NMDAR function is mediated by LRP-dependent activation of Src kinase; adaptation of NMDAR function occurs after activation of a NOS/sGC/PKG signaling pathway leading to RhoA/ROCK-mediated remodeling of the actin cytoskeleton. Adaptation of NMDAR function may be a neuroprotective mechanism to reduce excess Ca2+ influx and prevent neurotoxicity. These studies provide molecular and temporal detail of the dynamic changes in NMDAR function following exposure to Tat and offer insight into potential therapeutic targets for the treatment of HAND.