Browsing by Subject "NMDA"

Now showing 1 - 3 of 3
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    Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.
    (2011-09) Sullivan, Steven J.
    The N-methyl D-aspartate (NMDA) receptor coagonist D-serine is important in a number of different processes in the central nervous system, ranging from synaptic plasticity to disease states, including schizophrenia. In the retina, light-evoked responses of retinal ganglion cells are shaped in part by NMDA receptors which require a coagonist for activation. There is debate over whether glycine or D-serine is the endogenous coagonist of retinal ganglion NMDA receptors. I used a mutant mouse lacking functional serine racemase (SRKO), the only known D-serine synthesizing enzyme in mammals, to show that retinal ganglion cells depend on D-serine for NMDAR activation (chapter 1). Most changes in NMDA receptor currents during synaptic activity have been attributed to glutamate fluctuations against a steady background of coagonist, excluding the possibility of dynamic coagonist release. The retina is a particularly useful system to determine if coagonist release occurs in the nervous system, because it can be naturally stimulated with light. By saturating the glutamate binding site of NMDA receptors, I was able to measure coagonist release during light-evoked responses. Coagonist release was detected in retinal ganglion cell light responses and depended on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic AMPA receptors. Coagonist release was significantly lower in SRKO mice (chapter 2). By directly measuring extracellular D-serine using capillary electrophoresis, I demonstrated that D-serine can be released from the intact mouse retina through an AMPA receptor dependent mechanism (chapter 3). The collective works put forth in this thesis imply that activity-dependent modulation of D-serine availability may add an extra dimension to NMDA receptor coincidence detection in the central nervous system.
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    Endogenous modulation of addiction: chronic pain and the NMDA/NOS cascade.
    (2010-07) Wade, Carrie Lynn
    Opioid treatment for chronic pain is controversial due to abuse potential and perceived addiction potential. Because of perceptions of addiction from chronic opioid treatment for pain it is important to clearly understand the biological bases for a number of factors related to opioid therapy in the context of chronic pain, including the effectiveness of opioid treatment under distinct conditions chronic pain and alterations in the effectiveness of opioid treatment under distinct conditions of chronic opioid pharmacotherapy. One way to approach this question is to study the changes that occur with chronic pain and see how those changes parallel those that occur with opioid addiction. Our approach to address the questions raised above is to apply a combination of rodent models of pain and opioid self-administration. In the first phase of this study we examine changes in oral fentanyl self-administration under distinct conditions of chronic pain including inflammatory pain, neuropathic pain and an idiopathic pain model of sickle cell anemia. The second set of studies examines the potential for an endogenous modulator of the NMDA/NOS cascade to interact with adverse opioid events such as tolerance and addiction. We observed that mice with inflammatory pain, neuropathic pain and sickle cell anemia had differential fentanyl self-administration profiles following induction of mechanical hyperalgesia. In the second set of studies we observed that agmatine reduced opioid-induced tolerance and abolished self-administration behaviors. We also found that endogenous agmatine may have a neuroprotective effect on these opioid effects.
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    Mechanisms of HIV-associated neurotoxicity: Tat-induced synapse loss and recovery
    (2013-05) Brunner, Angela Haijung
    HIV infection is a worldwide pandemic. A debilitating neurological consequence of HIV infection is progressive cognitive decline, known as HIV-associated neurocognitive disorders (HAND). HAND afflicts up to 50% of all HIV patients to varying degrees, and as survival of HIV patients improves with current antiretroviral therapies, the prevalence of HAND is also increasing. This, coupled with the lack of current effective HAND therapies, creates a dire need to understand the mechanisms underlying the cognitive decline associated with HIV. HAND symptoms correlate closely with processes of neuronal injury, which are early events that precede overt neuronal death. One such injurious process is synapse loss. The HIV protein transactivator of transcription (Tat) is a neurotoxic viral protein released from infected cells into the central nervous system. Tat contributes to the pathologies seen in HAND patients, and induces loss of excitatory synapses between rat hippocampal neurons in culture. Using an innovative live cell imaging assay, our laboratory has previously shown that Tat induces reversible synapse loss via a pathway that is distinct from cell death. In this dissertation, I outline three studies that stem from the current knowledge involving Tat-induced synapse loss. These studies elucidated important information regarding the mechanisms by which HIV Tat exerts its neurotoxic effects, emphasizing the importance of subunit composition when determining toxic or beneficial effects of NMDA receptor activation as well as unmasking the importance of the postsynaptic density as the central target of Tat's effects. Furthermore, these studies highlight the reversibility of synapse loss and uncover a new role for the canonical NO/cGMP/PKG pathway in modulating synapse recovery downstream of GluN2B-containing NMDA receptors. Tat-induced synapse loss and subsequent recovery can correlate to symptoms of cognitive decline seen in HAND. Targeting these mechanisms can shed new light on therapeutic strategies to treat HAND patients.