Book of abstracts - British Neuroscience Association

57.09
Cognitive rigidity and altered interactions between memory
systems in a transgenic mouse model of Huntington’s disease
Ciamei A, Morton A J
Department of Pharmacology, University of Cambridge, Tennis Court
road, Cambridge CB2 1PD
In Huntington’s disease (HD), progressive cognitive deficits can
become as debilitating as motor impairment. Previous studies showed
that R6/2 mice have deficits in spatial and reversal learning. Here we
have tested R6/2 mice in different behavioural paradigms of learning
and memory that should allow us to study the functionality of
hippocampus- and striatum-based memory systems.
In the social transmission of food preference, R6/2 mice chose
flavours that had been eaten previously by a demonstrator mouse
(cued food) but were impaired in shifting their preference when a new
cued food was introduced in the task. Deficits were also seen in R6/2
mice in the active avoidance task where a mild footshock was paired
with a light. In the passive avoidance task, R6/2 mice learned to avoid
a place where they had previously received a footshock, but their
avoidance responses were not modulated by the intensity of the
footshock, as was observed with WT mice. Moreover, when ‘place
learning’ (hippocampus-dependent) and ‘response learning’ (dorsal
striatum-dependent) were studied in a modified version of the water
maze, R6/2 mice behaved mainly as ‘response learners’ while WT
mice adopted both place- and response-driven strategies to escape
the maze.
Our data show that R6/2 mice retain rigid cognitive abilities that allow
learning of socially and emotionally relevant experiences. Moreover,
they suggest an alteration in the interaction between striatum- and
hippocampus-based systems in tasks where these two systems act in
a competitive way to achieve learning and memory consolidation.
57.10
Seeking a mechanism of action for Mellissa Officinalis essential oil
treatment of agitation in human dementia
Chazot P L (1), Abhuhamdah S (1), Huang L(2), Ennaceur A(3), French D
(1), Elliott M S J(4), Perry E K (5), Ballard C (6), Francis P T (4), Lees G(2)
1. Centre for Integrative Neuroscience, Durham University,UK;2.Otago
Medical School, NZ;3.Sunderland Pharmacy School, UK;4.Wolfson Centre
for Age Related Diseases,King`s College, London,UK;5.Institute of Ageing
and Health, Newcastle University, UK;6.University of Northumbria,
Newcastle
Agitation is a severe and persistent feature of advanced dementia, which
affects both sufferers and carers alike. Atypical neuroleptic drugs have
frequently been used as treatments but often cause oversedation, social
withdrawal, enhanced risk of stroke and may exacebate cognitive decline.
Melissa officinalis (Mo) has been used historically for its calming and
attention maintenance properties and a large multi-centre trial to assess Mo
in late-stage AD patients will be commencing this year. In order to support
this trial, we have used radioligand binding and electrophysiology
techniques to address the hypothesis that the Mo may be a GABA-A
receptor modulator. Increasing concentrations of Mo (0.001-1 mg/ml) were
incubated with rat cortical brain membrane homogenates or the rat α1β2γ2
GABA-A receptor subtype expressed in HEK 293 cells, and a fixed
concentration of radioligand. Mo (IC50 = 0.03mg/ml) significantly displaced
[35S]-TBPS binding in both preparations, but had no effect upon
[3H]flunitrazepam, MK801, AMPA or nicotine binding to native membranes
up to 1mg/ml. Patch-clamp experiments on primary rat cortical cultures
demonstrated that Mo (0.1mg/ml) reduced currents through the GABA-A
channel but concurrently blocked the spontaneous synaptic traffic in the
cultured networks. We conclude that Mo essential oil does exert depressant
effects on neural activity, but that this is not a reflection of its disinhibitory
effect on the GABA-A complex. We are currently attempting to delineate
the active constituents within this oil, and assess the behavioural effects of
Mo in our unique all-in-one animal behavioural model .
Funded by the Alzheimer’s Disease Association (UK).
57.11
Characterisation of the binding properties of anti-beta amyloid
antibodies using optical biosensors
Chapman T D, Soden P E, Burbidge S A
Neurodegeneration Research Dept., Neurology and GI CEDD,
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex CM19 5AW, U.K.
In Alzheimer’s disease, the Beta-amyloid peptide has become a major
therapeutic target. Monoclonal antibodies generated against Betaamyloid
are often used to characterise the location and concentration
of Beta-amyloid in vivo, by IHC and ELISA respectively, but also have
potential in immunotherapeutic approaches. Optical biosensors can be
used to characterise the binding of these antibodies to Beta-amyloid,
in order to select the most advantageous clones. In these instruments
the mass of one binding partner is measured as it interacts with the
other partner, the later having already been immobilised on a sensor
surface. Data is presented that demonstrates the use of the SRU Bind
biosensor to map the epitopes of various antibodies along the Betaamyloid
peptide sequence. Antibodies directed towards the N-
terminus (6E10), mid-region (4G8) and C-termini (G210 and 5G5)
were observed. Data derived from the Biacore 3000 biosensor is also
shown that confirms the avidity, affinity and specificity of these
antibodies. The data shows how important it is for their respective
epitopes to be fully presented for binding, and not be masked by
incorrect immobilisation strategies, or possibly hidden within the
hydrophobic regions of fibrillar forms of the Beta-amyloid peptide.
57.12
The Effects of the Amyloid Peptide (Aβ1-42) and Fragments on
Recombinant Human Neuronal Nicotinic Acetylcholine Receptors
Craig M, Pym L, Buckingham S, Sattelle D
MRC Functional Genetics Unit, University of Oxford, Oxford, OX1 3QX
Alzheimer’s disease (AD) is the most prevalent form of dementia affecting
the elderly. It is widely believed that the amyloid peptide Aβ1-42 plays an
important role in AD progression, as its accumulation is toxic to neurons
both in vitro and in vivo. Aβ1-42 exerts subtype-selective actions on
nicotinic acetylcholine receptors (nAChRs) but it is not known what role is
played by an M35 residue in Aβ
be important in Aβ
Two-electrode voltage-clamp electrophysiology has been used to study the
actions on α7, α4β2 α3β4 recombinant human neuronal nAChRs
heterologously expressed in Xenopus laevis oocytes of full length Aβ 1-42
and Aβ peptide fragments, scrambled peptides, and Aβ 1-42 peptide
containing mutations of the methionine in position 35. Whereas Aβ 1-42 with a
M35C mutation had similar subtype specificity to wild-type Aβ 1-42, Aβ 1-42 with
a M35V substitution reduced the peak amplitude of ACh-induced currents
recorded from α4β2 nAChRs, but did not affect those recorded from α7 or
α3β4 receptors. Interestingly, the Aβ 25-35 fragment, which is often used as
an experimental mimetic of the full length peptide, did not display subunit
specificity. Our results suggest that that the amino acid in position 35 of
Aβ 1-42 is an important determinant of the subtype-specificity of the actions of
this peptide on human recombinant α7, α4β2 α3β4 nAChRs. We are
also exploring the actions of full length Aβ peptide and the neuroprotective
properties of nicotinic ligands using a human neuroblastoma cell line (SH-
SY5Y).
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