Modulation of Spontaneous Neural Network Bursting in Newborn Rat Brain Slices by Extracellular Calcium, Methylxanthines, and Opioids

  • Author / Creator
    Kantor, Chase M
  • Spontaneous neuronal bursting appears to be pivotal for brain maturation. This thesis studied such synchronized neural network oscillations in immature newborn rat hippocampus, cortex, and locus coeruleus. For this, horizontal brain slices were generated for (simultaneous) suction electrode recording of extracellular population bursting in these structures and monitoring their electrical activity indirectly at cellular resolution via imaging of associated cytosolic Ca2+ rises. In a first project, it was found that all rhythms were robust and stable for several hours in superfusate with close-to-physiological content of the neuroactive cations Ca2+ (1 mM) and K+ (3-4 mM) and were depressed by superfusate with elevated (1.5-3 mM) Ca2+ content and this inhibition was countered by raising K+ to 5-7 mM (‘Ca2+/K+ antagonism’). This thesis studied how the above hippocampal and cortical rhythms are affected by two classes of drugs that are frequently administered to (preterm) human infants: (i) the methylxantines caffeine and theophylline which are the gold standard for treatment of apneas of prematurity, but can evoke seizures, and (ii) opioids that are used for analgesia, but can depress breathing by inhibiting medullary respiratory network bursting. It was found that submillimolar bath-applied methylxanthine tended to increase the rate and/or amplitude of hippocampal and cortical bursts. At low millimolar doses, they suppressed normal rhythm in both areas and evoked large amplitude rhythmic seizure-like discharges. Similar seizure-like discharges were evoked in the hippocampus, but not cortex, by bath-application of 1-10 µM of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), which blocked locus coeruleus rhythm. In summary, the findings indicate that hippocampal, cortical and locus coeruleus networks in newborn rat horizontal slices show robust bursting in solution with close-to-physiological extracellular Ca2+ and K+ levels. Methylxanthines cause seizure-like discharges at doses that are likely higher than in extracellular brain tissue in vivo during clinical application. Opioids exert their typical inhibitory action on locus coeruleus neurons; however, they do not suppress bursting in cortex and hippocampus, but rather evoke hyperexcitability in the latter area. Potential mechanisms of methylxantine- and opioid-evoked perturbation of network oscillations are discussed including potential consequences for maturation of these neural circuits.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Physiology
  • Supervisor / co-supervisor and their department(s)
    • Ballanyi, Klaus (Physiology)
  • Examining committee members and their departments
    • Cherubini, Enrico (SISSA, Neurobiology - External)
    • Karpinski, Edward (Physiology)
    • Gosgnach, Simon (Physiology)
    • Nguyen, Peter (Physiology)
    • Harvey, Steve (Physiology - Chair)