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Neuromodulation of heterosynaptic plasticity in mouse hippocampus

  • Author / Creator
    Connor, Steven
  • The ability of synapses to undergo lasting changes in synaptic strength is considered the primary cellular mechanism for associative memory formation in the mammalian brain. Synapses in the hippocampus, a brain structure required for new memory genesis, exhibit a remarkable capacity for activity-dependent modification known as "synaptic plasticity". Our understanding of the neurobiological correlates of learning and memory has been significantly advanced through the study of one particular form of hippocampal synaptic plasticity known as long-term potentiation (LTP). As LTP has been linked to long-term memory formation, characterizing the mechanisms through which synaptic plasticity is regulated is crucial for advancing our understanding of the brains ability to encode and store information. Hippocampal synaptic plasticity and long-term memory can both be enhanced through activation of neuromodulatory receptors. Noradrenaline is an endogenous neuromodulatory transmitter which is secreted in response to novelty and arousing experiences. Neuromodulatory receptor stimulation can influence synaptic plasticity in a cell-wide manner known as heterosynaptic plasticity. Beta-adrenergic receptor (β-AR) stimulation results in the engagement of downstream signaling cascades capable of augmenting synaptic function. The present thesis identifies mechanisms through which β-ARs enhance heterosynaptic plasticity using electrophysiological recording methods in mouse hippocampal slices. I found that inducing homosynaptic LTP by pairing high-frequency stimulation with beta-adrenergic receptor activation lowered the threshold for heterosynaptic LTP. This form of heterosynaptic plasticity was altered in a mouse model of Fragile X Syndrome (FXS) which was the basis for my second project. When beta-adrenergic receptor-dependent LTP was induced in hippocampal slices from Fragile X mental retardation knockout mice, heterosynaptic LTP was enhanced relative to wild-type littermate controls. My final project investigated the mechanisms through which β-ARs and muscarinic receptors synergistically regulate synaptic plasticity. Co-application of beta-adrenergic and muscarinic receptor agonists enhanced LTP induced by a low-frequency stimulation protocol (5 Hz, 5 s). This form of LTP requires extracellular signal-regulated kinase and protein synthesis. Thus, I was able to further characterize how different neuromodulatory receptors can co-facilitate the induction of enduring synaptic plasticity which is considered the cellular basis for formation of new memories

  • Subjects / Keywords
  • Graduation date
    2011-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3XM8G
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Nguyen, Peter (Physiology)
  • Examining committee members and their departments
    • Todd, Kathryn (Neuroscience)
    • Ali, Declan (Biological Sciences)
    • Bains, Jaideep (Neuroscience)
    • Funk, Greg (Physiology)