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Search Results: 1 - 6 of 6 matches for " Doireann MacDermott "
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Bruce Bennett
Doireann MacDermott
Coolabah , 2012,
Abstract:
Functional identification of NR2 subunits contributing to NMDA receptors on substance P receptor-expressing dorsal horn neurons
Chi-Kun Tong, Edward J Kaftan, Amy B MacDermott
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-44
Abstract: NMDA receptors in the spinal cord dorsal horn are key elements in the initiation of changes in synaptic strength [1] and pain hypersensitivity [2,3]. These receptors consist of two obligatory NR1 subunits and two NR2 subunits, of which there are four types encoded by distinct genes: NR2A, NR2B, NR2C and NR2D [4]. The incorporation of different NR2 subunits has a major impact on the functional properties of the NMDA receptor, critically influencing agonist and antagonist affinity, receptor deactivation kinetics, channel conductance and interactions with intracellular proteins [3]. Additionally, NMDA receptors with NR2A or NR2B show higher Mg2+ sensitivity at negative membrane potentials than those with NR2C or NR2D [5,6].Involvement of NMDA receptors in dorsal horn function has been demonstrated through experiments interfering with expression of different NMDA receptor subunits. Knockdown of the NR1 subunit of NMDA receptors to eliminate functional NMDA receptors in the spinal cord reduces hyperalgesia and allodynia in a number of animal models but does not alter acute pain responses [7-9]. NR2A knockout mice show some reduced forms of hypersensitivities [10-12]. However, these NR2A knockouts display normal acute pain responses [12], formalin-induced hyperalgesia [13] and nerve ligation or injury-induced allodynia [14,15]. NR2B knockout mice do not survive postnatally [16,17], therefore NR2B specific antagonists have been used to study the role of this protein in pain hypersensitivity. Intrathecal administration of NR2B antagonists blocks or decreases PGE2 or NMDA induced allodynia [11] as well as capsaicin-induced hyperalgesia [18]. NR2D knockout mice fail to develop nerve ligation [12], PGE2 [19] or PGF2alpha-induced allodynia [11,20]. Overall, these data suggest that different NR2 subunits are involved in dorsal horn circuits important for the development of hyperalgesia or allodynia but their specific functions remain unresolved.Lamina I of the spinal cord is a c
Maturation of Spinal Motor Neurons Derived from Human Embryonic Stem Cells
Tomonori Takazawa, Gist F. Croft, Mackenzie W. Amoroso, Lorenz Studer, Hynek Wichterle, Amy B. MacDermott
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040154
Abstract: Our understanding of motor neuron biology in humans is derived mainly from investigation of human postmortem tissue and more indirectly from live animal models such as rodents. Thus generation of motor neurons from human embryonic stem cells and human induced pluripotent stem cells is an important new approach to model motor neuron function. To be useful models of human motor neuron function, cells generated in vitro should develop mature properties that are the hallmarks of motor neurons in vivo such as elaborated neuronal processes and mature electrophysiological characteristics. Here we have investigated changes in morphological and electrophysiological properties associated with maturation of neurons differentiated from human embryonic stem cells expressing GFP driven by a motor neuron specific reporter (Hb9::GFP) in culture. We observed maturation in cellular morphology seen as more complex neurite outgrowth and increased soma area over time. Electrophysiological changes included decreasing input resistance and increasing action potential firing frequency over 13 days in vitro. Furthermore, these human embryonic stem cell derived motor neurons acquired two physiological characteristics that are thought to underpin motor neuron integrated function in motor circuits; spike frequency adaptation and rebound action potential firing. These findings show that human embryonic stem cell derived motor neurons develop functional characteristics typical of spinal motor neurons in vivo and suggest that they are a relevant and useful platform for studying motor neuron development and function and for modeling motor neuron diseases.
NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn
Hiroaki Shiokawa, Edward J Kaftan, Amy B MacDermott, Chi-Kun Tong
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-26
Abstract: Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations.Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.The large majority of neurons in the superficial dorsal horn are local circuitry interneurons, including both excitatory and inhibitory interneurons [1]. Inhibition controls the flow of sensory input through mono and polysynaptic excitatory pathways to dorsal horn projection neurons and thus to higher brain centers. Sensory inputs include the modalities of pain, itch, temperature, and some mechanosensation. A good example of the interplay between excitation and inhibition in the dorsal horn is revealed by the disinhibition that sometimes accompanies peripheral nerve injury. This disinhibition produces allodynia, a painful response to a stimulus that is usually non-painful or innocuous. The disinhibition driving the behavioral phenomenon of allodynia can be mimicked by intrathecal administration of the GABAA receptor antagonist, bicuculline, or the glycine receptor antagonist strychnine [2-5]. These behavioral changes associated with disinhibition are consistent with a chronic pain condition.NMDA receptors are expressed at glutamatergic synapses throughout the superficial dorsal horn and have been implicated in driving the new excitatory activity that accompanies dis
Molecular pain, a new era of pain research and medicine
Jianguo Gu, Min Zhuo, Michael Caterina, Amy B MacDermott, Annika Malmberg, Volker Neugebauer, Megumu Yoshimura
Molecular Pain , 2005, DOI: 10.1186/1744-8069-1-1
Abstract: The word pain is thought to derive from the Latin word poena, meaning punishment. An emotional reaction to a punishment might have been what Aristotle experienced, as he defined pain as an emotional event. René Descartes, the seventeenth-century philosopher and scientist, pictured a pain pathway consisting of a thread with two ends: one end is in a peripheral part of the body, for example a toe, and the other end is a bell in the brain. According to this picture, fire touching a toe pulls the thread, and rings the bell to sound a warning in the brain. Over the past decades, and in the current Decade of Pain Control and Research (2001–2010), pain research has undergone major changes, from a system level to cellular, subcellular and molecular levels. A new era of molecular pain research is now emerging, and the journal Molecular Pain is dedicated to this modern phase of pain research.Recent advances in pain research are in large part due to the rapid progress in neuroscience, molecular biology, and other fields in the life sciences. Breakthroughs in biomedical technologies have allowed us to address many important issues about pain, enriching our knowledge about the mechanisms by which sensory signals including pain are initiated, encoded, conducted, transmitted, modulated, and perceived. For example, sensory molecular biology has led to the molecular cloning and identification of a number of receptors involved in thermal, mechanical, and nociceptive signalling at the periphery, some of which have been targeted for pain management. Modern electrophysiology has been used to demonstrate the critical roles of synaptic plasticity in pain processing in the spinal cord and the brain. Long-term potentiation and long-term depression at synapses of central sensory regions have delineated the 'memory of pain' by neuronal circuitry along pain transmitting pathways. Functional imaging of supraspinal areas has revealed central areas related to pain processing (for example, areas c
Characterization of sensory neuron subpopulations selectively expressing green fluorescent protein in phosphodiesterase 1C BAC transgenic mice
Carole Torsney, Rebecca L Anderson, Kerry-Anne G Ryce-Paul, Amy B MacDermott
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-17
Abstract: Using double labeling immunofluorescence, we demonstrate GFP expression in specific subpopulations of primary sensory neurons and a distinct neuronal expression pattern within the spinal cord dorsal horn. In the dorsal root ganglia, their distribution is restricted to those subpopulations of primary sensory neurons that give rise to unmyelinated C fibers (neurofilament 200 negative). A small proportion of both non-peptidergic (IB4-binding) and peptidergic (CGRP immunoreactive) subclasses expressed GFP. However, GFP expression was more common in the non-peptidergic than the peptidergic subclass. GFP was also expressed in a subpopulation of the primary sensory neurons immunoreactive for the vanilloid receptor TRPV1 and the ATP-gated ion channel P2X3. In the spinal cord dorsal horn, GFP positive neurons were largely restricted to lamina I and to a lesser extent lamina II, but surprisingly did not coexpress markers for key neuronal populations present in the superficial dorsal horn.The expression of GFP in subclasses of nociceptors and also in dorsal horn regions densely innervated by nociceptors suggests that Pde1c marks a unique subpopulation of nociceptive sensory neurons.Sensory information is conveyed from the periphery to the central nervous system via a heterogeneous population of primary sensory neurons that have their cell bodies in dorsal root ganglia (DRG). Sensory information is then processed within the complex neuronal circuitry of the dorsal horn before it is relayed to higher centers and 'perceived'. Key to our understanding of sensory processing is mapping the organization or 'wiring' of neurons within sensory pathways. This goal has recently been aided by the creation of mice expressing fluorescent markers within specific sensory neuron subpopulations [1-6]. Here we characterize mice in which green fluorescent protein (GFP) is specifically expressed in cyclic nucleotide phosphodiesterase 1C (Pde1c) positive cells using bacterial artificial chromosome (
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