Bibi, Shakila (2010) Fabrication and use of D-serine biosensors for characterising D-serine signalling in rat brain. PhD thesis, University of Warwick.

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Abstract

D-serine is a co-agonist at NMDA receptors in the brain but the study of this amino
acid is restricted by current techniques. I have designed highly sensitive D-serine
biosensors that permit accurate real-time recordings of D-serine in the brain in a
selective manner. I demonstrate that these tools are ideal for investigating factors
involved in the regulation of this amino acid and the role that D-serine plays in
excitotoxic cell death mediated via NMDA receptors.
I have established that the extracellular basal concentrations of D-serine in the rat
brain are heterogeneous and vary even within brain structures. This suggests that Dserine
is an important regulatory constraint for NMDA receptor activation, as
receptor response can only be potentiated in regions with low D-serine content.
Additionally, I show that these microelectrode biosensors have the potential to be
used in vivo to detected extracellular D-serine levels.
In addition I have observed real-time activity dependent regulation (both loss and
release) of D-serine by ionotropic glutamate receptor agonists AMPA, NMDA and
kainate, PAR1-agonist TFFLLRNH2 and high frequency stimulation in vitro in a
number of brain areas. A decrease in D-serine concentration is potentially
neuroprotective as it suggests a reduction in NMDA receptor activation. However,
D-serine release can be observed in regions where the co-agonist site of the NMDA
receptor is likely to be already saturated implying an alternative function of D-serine
in the brain. These findings indicate multifaceted regulation of this amino acid that is
brain-region specific.
Finally, I have investigated the role of D-serine release during models of stroke
(hypoxia and ischemia) and found that D-serine levels are reduced in brain regions
deprived of oxygen. This is ultimately neuroprotective as it will reduce over -
excitation at the NMDA receptor during these insults. In the more profound model of
stroke, oxygen-glucose deprivation, D-serine is eventually released. This release
precedes anoxic depolarisation and could therefore contribute to its initiation via
enhanced activation of the NMDA receptor.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history Q Science > QL Zoology
Library of Congress Subject Headings (LCSH):	Serine, Biosensors, Cell death, Brain -- Physiology, Rats -- Physiology
Official Date:	June 2010
Dates:	Date Event June 2010 Submitted
Institution:	University of Warwick
Theses Department:	Department of Biological Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Dale, Nicholas
Sponsors:	University of Warwick
Extent:	184 leaves : ill., charts
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/3897

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