Book of abstracts - British Neuroscience Association

64.08
Modulation of ketamine-induced blood-oxygen level dependent
(BOLD) responses by an AMPA antagonist’
de Groote C, McKie S, Deakin B, Williams S
Neuroscience and Psychiatry Unit, and Imaging Science and
Biomedical Engineering; University of Manchester, Manchester, M13
9PT, United Kingdom
The glutamate hypothesis of schizophrenia proposes an important role
for glutamate in the symptoms of the disease, which can be mimicked
experimentally by ketamine (KET). We previously established
localised changes in blood-oxygenation level dependent (BOLD)
contrast in the rat brain in regions relevant to schizophrenia using
direct pharmacoMRI. To investigate whether KET-induced BOLD
changes are due to glutamate release and subsequent stimulation of
post-synaptic glutamate receptors, we pretreated with GYKI52466, an
AMPA antagonist. Young adult male rats were anaesthetised with
isoflurane (1.5%) and placed in a 7T horizontal magnet. BOLD
sensitive T2*-weighted images were acquired using a gradient echo
sequence. Ten minutes before the start of functional imaging, vehicle
or GYKI52466 (10 mg/kg) was injected (i.p.). In total 72 volumes of 70
seconds were collected, with 18 volumes (20 minutes) of baseline
scans and 52 post-injection scans (63 minutes). KET (30 mg/kg s.c.)
was injected at the start of volume 19. Data were pre-processed and
analyzed using a general linear model in SPM2. Drug and time
interactions were investigated using a one way ANOVA (uncorrected,
p<0.01). GYKI52466 pre-treatment reduced KET-induced activations
in the thalamus, hippocampus, auditory cortex, cingulate cortex and
retrosplenial cortex. GYKI52466 pre-treatment enhanced KET-induced
BOLD changes in the striatum, somatosensory cortex, colliculus, and
somatosensory cortex. Our study demonstrates that pre-treatment
with the AMPA antagonist GYKI52466 reduces KET-induced BOLD
changes in key areas of the rat brain. This supports recent findings for
a role of enhanced glutamatergic transmission in schizophrenia.
CdG was supported by a NARSAD YIA Award
65.01
Confocal microendoscopic analysis of neuromuscular phenotypes in
ethylnitrosourea (ENU)-mutagenised WldS mice.
Wong F, Fan L, Coleman M P, Blanco G, Ribchester R R
MRC Mary Lyon Centre, Harwell and Centre for Neuroscience Research, 1
George Square, Edinburgh.
Severing the motor nerve supply to skeletal muscle normally triggers rapid
Wallerian degeneration. In homozygous WldSmutant mice, axon
degeneration is actively delayed by expression of an Nmnat/Ube4b
chimeric gene: disconnected motor nerve terminals persist for several days;
and axons are preserved for up to three weeks, rather than 24-72 hours
characteristic of wild-type mice. However, in heterozygous WldS mice
axotomy-induced degeneration of presynaptic motor nerve terminals occurs
at a normal rate. This observation supports a compartmental model of
neurodegeneration, according to which cell bodies, axons and nerve
terminals degenerate in response to surgical or chemical trauma by
different sub-cellular mechanisms. Discovery of other gene mutations that
selectively protect synapses would validate this hypothesis. We are
attempting this in a high-throughput screen of mice mutagenised by
ethylnitrosourea (ENU), designed to reveal covert neuromuscular
phenotypes after axotomy in vivo. We perform a novel phenotypic assay:
650µm or 1500 µm tipped fibre-optic probes connected to a Cellvizio
confocal microendoscope (Mauna Kea Technologies, Paris). The
procedure is minimally invasive yet can resolve intact and degenerating
axons and synapses in living anaesthetised (halothane/N20) transgenic
mice that co-express yellow fluorescent protein (YFP) in motor neurones as
a biomarker. We use WldS mice as a sensitized background, examining for
either additive synaptic protection or block of axonal protection following
axotomy in the F1 offspring of the ENU x thy1.2:YFP16-WldS crossbred
mice. To date, we have studied more than 23 ENU lines but none has yet
shown evidence of interaction with the WldS/+ phenotype.
65.02
Strong protection of annulospiral Ia afferent axon terminals from
Wallerian degeneration in muscle spindles of WldS mutant mice.
Oyebode O R O, Singhota J, Gillingwater T H, Ribchester R R
Centre for Neuroscience Research, University of Edinburgh, EH8 9JZ
The Wld S mouse is a mutant in which axons survive several weeks
after transection, by virtue of expression of a chimeric Nmnat1/Ube4b
protein. The Wld S phenotype extends to axons in both CNS and
PNS. Wld S also protects presynaptic terminals but studies on this
have been limited to neuromuscular junctions and synapses in the
brain. There are no published data on the degeneration of sensory
axons and their terminals in these mice. Here we report that
annulospiral endings of Ia afferent axons are very strongly preserved
after axotomy in mice. Homozygous or heterozygous Wld S mice
crossbred with thy1.2-CFP transgenic mice were sacrificed 1-20 days
after sciatic nerve transection under halothane/N 2 O inhalation
anaesthesia. Fluorescence microscopy of whole mount preparations
of lumbrical muscles revealed excellent preservation of annulospiral
endings on muscle spindles for at least 10 days after axotomy. No
significant difference was detected in the protection with age or gene
dose, in contrast to the protection of motor nerve terminals, which
degenerated rapidly in heterozygous and >4-month old
homozygous Wld S mice. However, Ia afferent axons were protected
for longer than their annulospiral endings. Quantitative image analysis
of reconstructions from confocal projections (z-series) also suggested
that slow degeneration of annulospiral endings in Wld S mice occurs
by intercalary loss of their intrafusal annuli, rather than either retraction
or fragmentation, as shown by axotomised motor terminals. Thus, like
motor terminals, sensory endings are less well protected by WldSthan
their parent axons, but sensory endings are protected better and
longer than motor nerve endings.
65.03
Neuroprotective properties of the non-peptidyl radical scavenger
IACVITA in rats following tMCAO.
Nurmi A, Puoliväli J, Pussinen R, Soleti A, Bagate K, Paolini M, Riccardino
F, Grundy R I, Yrjänheikki J
Cerebricon Ltd, Microkatu 1, FIN-70211 Kuopio, FINLAND, , Medestea
Research & Production S.p.A., Via Cernaia 31, 10121 Torino, , Forenap
Pharma, France., , University of Bologna,, Bologna,, Italy., , ,
Substantial evidence exists to suggest that reactive free radicals are
generated during brain ischemia. Anti-oxidant neuroprotective agents have
also been found to be effective in animal models of stroke. However,
clinical trials have proved inconsistent. Here we investigated the effect of a
novel radical scavenger, IACVITA, on cerebral infarct volume and sensorymotor
performance in a rat transient Middle Cerebral Artery Occlusion
model (tMCAO). Male Sprague-Dawley rats were subjected to 90 min
tMCAO and treated with i.p. or i.v. injections of vehicle or IACVITA after the
onset of tMCAO. Sensory-motor performance was evaluated daily by 7 and
28 point Neuroscore tests (NS). Cerebral infarct volume was evaluated at
72 h after tMCAO. Rats exhibited a significant decrease in 7 and 28 point
NS during the 3-day monitoring period. Rats treated with IACVITA i.p. (1 or
6 h after the onset of tMCAO) or i.v. (1 h after the onset of tMCAO) showed
significant improvement in 7 and 28 point NS after tMCAO during the 3-day
follow-up period when compared to vehicle treated rats. Cerebral infarct
volumes were significantly decreased compared to vehicle in rats receiving
IACVITA i.p. 1 or 6 h or i.v. 1 h after the onset of tMCAO, which supported
observations from the 7 and 28 point NS tests. These results demonstrate
that IACVITA has unique neuroprotective properties with a wide therapeutic
window in 90 min tMCAO model in rats, which is reflected in the improved
sensory-motor performance and reduced infarct volumes.
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