Molecular mechanisms of synaptic transmission and plasticity in spinal sensory pathways
Author
Summary, in English
An intense, potentially tissue-damaging (noxious) stimulus may lead to enhanced pain sensation of subsequent noxious stimuli (hyperalgesia) and to the perceiving of innocuous stimuli as painful (allodynia). This is thought to result to a large extent from strengthening of synapses established by primary afferent fibers onto spinal cord dorsal horn neurons. Here we investigated, using the postembedding immunogold technique and electron microscopy in conjunction with neuronal tracing of primary afferent fibers, the molecular basis of transmission of primary afferent synapses in the naïve state and after acute noxious stimulation that induces hyperalgesia.
Primary afferent synapses use glutamate as a neurotransmitter, but a transmitter role has also been proposed for aspartate, which may, by acting selectively at NMDA-type glutamate receptors, be specifically involved in plasticity. In paper I, aspartate is found to occur only at low levels and, unlike glutamate, not in association with synaptic vesicles in primary afferent terminals in the dorsal horn, suggesting that these terminals lack a transmitter pool of aspartate, which may thus be involved solely in general metabolism.
Autophosphorylated CaMKII (pCaMKII) may, in addition to its established role in synaptic plasticity, also be important for maintenance of synaptic strength. This would imply constitutive presence of pCaMKII at most synapses. In paper II it is shown that a large majority of primary afferent synapses indeed contains basal levels of pCaMKII concentrated in the postsynaptic density, but that nociceptive primary afferent synapses contain considerably higher levels than those formed by low-threshold tactile afferent fibers.
In paper III we show that after noxious stimulation, CaMKII and pCaMKII are increased postsynaptically at synapses from peptidergic nociceptors, but, unexpectedly, instead decreased at synapses formed by non-peptidergic nociceptors, while being unaltered at those from low-threshold tactile fibers.
Paper IV investigates whether AMPA-type glutamate receptors are similarly altered at primary afferent synapses after noxious stimulation. However, at synapses from non-peptidergic nociceptors, postsynaptic AMPA receptor expression was increased (indicating potentiation of such synapses), whereas no changes were found at peptidergic nociceptive or low-threshold afferent synapses.
In conclusion, the present observations suggest that basal primary afferent synaptic transmission is mediated by glutamate, but not by aspartate, and involves constitutive autophosphorylation of CaMKII, whereas distinct modes of molecular plasticity, that appear to contrast with current models of long-term potentiation, are induced at different populations of nociceptive synapse in a common model of hyperalgesia.
Primary afferent synapses use glutamate as a neurotransmitter, but a transmitter role has also been proposed for aspartate, which may, by acting selectively at NMDA-type glutamate receptors, be specifically involved in plasticity. In paper I, aspartate is found to occur only at low levels and, unlike glutamate, not in association with synaptic vesicles in primary afferent terminals in the dorsal horn, suggesting that these terminals lack a transmitter pool of aspartate, which may thus be involved solely in general metabolism.
Autophosphorylated CaMKII (pCaMKII) may, in addition to its established role in synaptic plasticity, also be important for maintenance of synaptic strength. This would imply constitutive presence of pCaMKII at most synapses. In paper II it is shown that a large majority of primary afferent synapses indeed contains basal levels of pCaMKII concentrated in the postsynaptic density, but that nociceptive primary afferent synapses contain considerably higher levels than those formed by low-threshold tactile afferent fibers.
In paper III we show that after noxious stimulation, CaMKII and pCaMKII are increased postsynaptically at synapses from peptidergic nociceptors, but, unexpectedly, instead decreased at synapses formed by non-peptidergic nociceptors, while being unaltered at those from low-threshold tactile fibers.
Paper IV investigates whether AMPA-type glutamate receptors are similarly altered at primary afferent synapses after noxious stimulation. However, at synapses from non-peptidergic nociceptors, postsynaptic AMPA receptor expression was increased (indicating potentiation of such synapses), whereas no changes were found at peptidergic nociceptive or low-threshold afferent synapses.
In conclusion, the present observations suggest that basal primary afferent synaptic transmission is mediated by glutamate, but not by aspartate, and involves constitutive autophosphorylation of CaMKII, whereas distinct modes of molecular plasticity, that appear to contrast with current models of long-term potentiation, are induced at different populations of nociceptive synapse in a common model of hyperalgesia.
Department/s
Publishing year
2006
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Document type
Dissertation
Publisher
Faculty of Medicine, Lund University
Topic
- Basic Medicine
Keywords
- neurophysiology
- neuropsychology
- Neurology
- electron microscopy
- synaptic plasticity
- synapse
- pain
- spinal cord
- hyperalgesia
- Neurologi
- neuropsykologi
- neurofysiologi
Status
Published
Research group
- Neurophysiology
Supervisor
- Jonas Broman
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 91-85481-42-4
Defence date
25 February 2006
Defence time
10:00
Defence place
Segerfalksalen, BMC A10, Wallenberg Neurocentrum, Sölvegatan 17
Opponent
- Andrew Todd (Professor)