Development of adenosine signalling in the cerebellum
Atterbury, Alison (2010) Development of adenosine signalling in the cerebellum. PhD thesis, University of Warwick.
WRAP_THESIS_Atterbury_2010.pdf - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Official URL: http://webcat.warwick.ac.uk/record=b2490617~S15
The release and clearance of adenosine are reasonably well-documented in the
mature CNS but relatively little is known about how adenosine signalling changes
during postnatal development. The activation of presynaptic A1 receptors (A1R) at
cerebellar parallel fibre terminals is known to inhibit synaptic transmission and the
expression of A1R has been observed in mature rat cerebellar slices. However its
distribution during development or in relation to parallel fibre–Purkinje cell (PF-PC)
synapses has not previously been described. In the mature cerebellum blockade of
presynaptic A1R at PF-PC synapses enhances synaptic transmission suggesting an
inhibitory adenosine tone and an extracellular purine tone is detectable with
microelectrode biosensors under basal conditions. The active release of adenosine
can be stimulated with trains of activity in the molecular layer of mature slices
although this does not appear to be a source of the basal extracellular adenosine tone.
This study used immunohistochemistry to determine the distribution of A1R at PFPC
synapses in cerebellar slices at postnatal day 3 prior to PF-PC synapse formation,
postnatal days 8-14 and postnatal days 21-28. This study also used cerebellar slices
from rats at postnatal days 9-14 to investigate the pharmacological profile of the
immature rat PF-PC synapse with electrophysiology and microelectrode biosensors.
The immunohistochemistry suggests that A1R are widely distributed across Purkinje
cell bodies and their dendrites and within the granule layer of the cerebellum and that
its expression does not change during development. The same staining patterns were
also observed prior to PF-PC synapse formation.
Application of adenosine resulted in a variable A1R-mediated inhibition at immature
PF-PC synapses. This did not appear to be gender-specific or correlated with age of
rat and the synapses otherwise appeared identical in their properties. The
comparison of log concentration-response curves generated for an A1R agonist
suggested that some A1R may have a lower efficacy at this stage of development.
Blockade of presynaptic A1R at immature PF-PC synapses suggested that an
inhibitory adenosine tone is low or absent at this stage of development and is not the
result of a low A1R expression or developmental differences in A1R efficacy.
Inhibition of adenosine clearance via adenosine deaminase, adenosine kinase and
equilibrative transporters had little effect on synaptic transmission suggesting that
little adenosine is moving between the intracellular and extracellular spaces under
basal conditions in immature slices. Active adenosine release measured by
electrophysiology and microelectrode biosensors could be stimulated with hypoxia in
immature slices but this was delayed and slower in comparison to the release
observed in mature slices. Adenosine could not be actively released at immature PFPC
synapses in response to electrical stimulation in the molecular layer.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QP Physiology|
|Library of Congress Subject Headings (LCSH):||Adenosine, Cerebellum -- Evolution, Cerebellum -- Physiology, Cellular signal transduction, Synapses|
|Official Date:||August 2010|
|Institution:||University of Warwick|
|Theses Department:||Department of Biological Sciences|
|Sponsors:||Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC) ; University of Warwick|
|Extent:||xvi, 211,  leaves : ill., charts|
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