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Browsing by Subject "Synaptic plasticity"

Now showing 1 - 3 of 3
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    Characterizing cellular mechanisms of cocaine-evoked synaptic plasticity in the nucleus accumbens
    (2017-12) Ingebretson, Anna
    Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within mesocorticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During abstinence from cocaine treatment, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, reverses and depotentiates enhanced AMPAR signaling, demonstrating that cocaine bidirectionally alters excitatory synaptic transmission in the NAc. Understanding the neurobiological mechanisms underlying drug-induced synaptic adaptations in the NAc could provide targets for developing strategies to reverse or offset maladaptive processes driving long-lasting vulnerability to relapse. However, the detailed cellular signaling mechanisms mediating cocaine-evoked plasticity have not been well-characterized. Using pharmacological approaches in combination with patch-clamp recordings in the NAc, we investigated the role of candidate signaling factors that mediate adaptive synaptic plasticity in the striatum. Among these, activation of group I metabotropic receptors (mGluR1/5) play a prominent role in synaptic depression at excitatory synapses, and furthermore are implicated in models of relapse to drug-seeking. Consistent with this, we found that activation of mGluR5 is necessary for cocaine-induced depotentiation of AMPAR signaling in the NAc. Downstream of mGluR1/5 receptors, mobilization of endogenous cannabinoids (eCBs) is an important factor modulating excitatory synaptic strength. Dopamine receptors in the striatum also broadly modulate synaptic transmission at glutamatergic terminals on MSNs, and are critically engaged by drugs of abuse. Both dopamine and eCB signaling were necessary factors in the induction of cocaine-induced synaptic plasticity in the NAc, suggesting that these neuromodulators may modify the responsiveness of MSNs to alterations in glutamatergic input induced by cocaine. Finally, we examined plasticity at synapses on specific MSN cell subpopulations, demonstrating that specific dopamine receptors on distinct cell types promote specific modifications in AMPAR synaptic function following cocaine experience. These neuromodulatory signaling mechanisms may serve to gate the induction of plasticity at glutamatergic afferents on NAc MSNs by converging on common factors that control the sensitivity of MSNs to excitatory input, ultimately driving addiction-related behavior.
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    Chronic morphine treatment-modulated trafficking of AMPA receptors: a potential mechanism for drug addiction
    (2012-08) Kam, Yuet Fong
    Morphine is the benchmark analgesic for treating chronic pain. However, its clinical uses are hindered by its highly addictive nature, as chronic treatment with the drug will produce physical and psychological dependence upon the cessation of use. Drug craving is the main driving force for relapse after prolonged periods of abstinence, and represents an enormous challenge for the treatment of drug addiction. Since addiction is a long-term behavioral alteration, it is believed that addictive drugs produce reorganization of specific neural circuits and adjustment of synaptic strength. The underlying mechanisms of these neural adaptations may represent a promising target for prevention and/or treatment of addiction, but the detailed mechanisms of these processes remain unclear. Therefore, the main goals of this work are to delineate signaling pathways controlling morphine-induced neural adaptations and investigate their functional role in opiate addictive behaviors. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are postsynaptic glutamate receptors, and are responsible for mediating most excitatory synaptic transmission under normal conditions. More importantly, the dynamic localization of AMPA receptors plays a critical role for modifying synaptic strength and synaptic morphology. Here, I hypothesized that regulation of AMPA receptor trafficking by morphine treatment underlies the drug-induced neural modulation implicated in the addiction process. Hence, the first part of this dissertation research examined whether and how chronic exposure to morphine modulates trafficking of surface GluR1 (a subunit of AMPA receptors) in primary hippocampal neurons. Using live-cell imaging techniques together with biochemical studies, I demonstrated that chronic exposure to morphine induced a significant loss of synaptic and extrasynaptic GluR1 by internalization. In mechanistic studies, I found that the GluR1 internalization was attributed to dephosphorylation of the receptor subunit at Ser845 following morphine treatment, but it did not result from altered neural network or NMDA receptor activation. Moreover, dephosphorylation of GluR1 at Ser845 was found to require morphine-evoked calcineurin activation. Therefore, calcineurin-dependent dephosphorylation of AMPA receptor and subsequent AMPA receptor internalization provides a novel mechanism for opioid-induced neural adaptations. The second part of this dissertation research attempted to link morphine's effects on GluR1 phosphorylation and endocytosis to addictive behavior, especially formation of memory for the environmental context of the drug experience, because recall of this memory by encountering the drug-paired cues triggers relapse to drug seeking. In this approach, a mutant mouse line was used, in which GluR1 at Ser845 was mutated to Ala (S845A) leading to an absence of morphine-induced GluR1 endocytosis. A behavioral test, conditioned place preference (CPP), was carried out to assess the ability of morphine to produce a positive association with environmental cues. I found that S845A mice were significantly slower to acquire morphine-induced CPP when compared to wild types (WT). This decreased sensitivity to morphine CPP in mutants was neither related to contextual memory deficits or abnormal locomotor activity, as there was no difference between WT and S845A mice in the contextual memory acquisition in the Morris water maze test or locomotion with or without morphine injection. To examine the persistence of morphine-associated contextual memory in the mutant mice, I also performed extinction tests on mice conditioned with 10 mg/kg morphine for four sessions, by which both WT and S845A mice exhibited similar CPP responses. Interestingly, a prolonged extinction was observed in S845A mutant mice, suggesting the S845A mutation either impaired the learning of the new conditioning or prolonged the retention of the old conditioning. Nevertheless, these results suggest that an alteration in GluR1 phosphorylation at Ser845 and subsequent receptor endocytosis/insertion are involved in acquisition and extinction of morphine CPP. Altogether, the present findings indicate that calcineurin-mediated GluR1-S845 dephosphorylation is required for morphine-induced internalization of GluR1-containing AMPA receptors, providing a molecular basis for the drug-induced neural modulation. This work also suggests that this regulation of GluR1 phosphorylation and trafficking by morphine is involved in the modulation of the drug-associated contextual memory, which reflects the involvement of AMPA receptor trafficking in the mechanisms underlying opiate-seeking behaviors.
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    The Role of High-Density Lipoproteins and Related Pathways in Alzheimer’s Disease
    (2017-12) Hottman, David
    Alzheimer’s disease (AD) is the most prevalent age-related dementia and will place an increasingly demanding burden on our healthcare system as the population ages. It has been firmly established that high plasma levels of high-density lipoprotein (HDL) protect against cardiovascular disease and accumulating evidence indicates that the beneficial role of HDL extends to the central nervous system. There are several important biological mechanisms that regulate HDL generation and metabolism/function. One is through the cholesteryl ester transfer protein (CETP), which transports cholesterol esters and triglycerides between different lipoprotein particles. Loss-of-function mutations in CETP are associated with better cognition in aging. To investigate the role of CETP in AD, human CETP transgenic mice were crossed with an Alzheimer’s mouse model, followed by biochemical and behavioral analyses. The results showed that CETP-induced modest decrease in plasma HDL levels was insufficient to affect brain amyloid pathology, neuroinflammation, or memory function. Next, to explore the therapeutic potential of a cardiovascular protective, HDL-mimetic-peptide called D-apoJ[113-122], AD mice were treated with the peptide. This treatment robustly reduced brain amyloid pathology and improved memory function in AD mice. Further analyses showed that D-apoJ[113-122] exerted its beneficial effects through reduction of cerebral vascular amyloid deposition and clearance of brain amyloid to plasma. Finally, prenyltransferase-deficient mice were used to investigate the role of protein prenylation in synaptic function. Prenylation is an important posttranslational lipid modification process that attaches isoprenoids (the intermediates in the cholesterol biosynthesis pathway) to target proteins. Electrophysiological/histochemical experiments showed that systemic or forebrain-specific deficiency of one particular prenyltransferase, geranylgeranyltransferase-1, caused marked impairment in hippocampal synaptic plasticity and decrease in neuronal dendritic spine density. Further analyses indicated that reduction of prenylation of certain small GTPases, which rely on prenylation for proper cellular localization and function, underlies the detrimental effects in these mice, as observed in aged mouse brains. These results corroborate the critical role of protein prenylation in synaptic function during development and in the adult brain. Taken together, findings from this research provide novel insights into the role of HDL and related pathways in the pathogenesis of AD, and offer new avenues to develop effective therapies for AD.