Book of abstracts - British Neuroscience Association

21.05
Spatial arrangement of cortical neurons and glia in autism.
Luthert PJ 1, McDermott CJ 1, Dean AF 2, Bailey A 3
1 Division of Pathology, Institute of Ophthalmology, London, UK, 2
Neuropathology, Addenbrookes Hospital, Cambridge, UK, 3
Department of Psychiatry, University of Oxford, UK,
Previously we identified relatively focal qualitative disturbances of
neuronal organisation in the cortex of individuals with autism.
Subsequently, Casanova and colleagues drew attention to
abnormalities of minicolumn arrangment in autism. In this study we
tested the hypothesis that there were distributed abnormalities of
spatial arrangement of neurons or glia in autism.
Using a photo-microscope with a stepping stage, sections from the
anterior cingulate gyrus, at the level of the genu of the corpus
callosum, and the occipito-temporal gyrus at the level of the pes of the
hippocampus were examined. X and Y coordinates of neurons and
glia were recorded. Probability density maps were then constructed by
taking each individual cell in turn and plotting the positions of its
neighbours. Neurons and glia were plotted separately. In this way it
was possible to generate a probability map giving the relative
likelihood of finding cells at a given distance and angle from any cell.
The analysis was carried out for each lamina.
Density maps generally had a central peak with smaller, approximately
symmetrical peaks either side. This pattern is consistent with a
minicolumnar organisation. The width of the central peak and the
distance from the central peak to those either side was measured. The
main finding was of a narrowing of the glial, but not neuronal, central
cluster width in individuals with autism in both areas examined.
These findings suggest that there may be a disturbance of glial,
neuronal interaction as part of the the neuroanatomical substrate of
autism.
22.01
Noradrenergic control of inflammatory processes in the CNS
Connor T J, McNamee E N
Neuroimmunology Research Group, School of Medicine & Trinity College
Institute of Neuroscience, University of Dublin, Trinity College, Dublin 2.
Evidence suggests that inflammation is a significant contributor to
pathology in a number of neurodegenerative disease states. In this regard,
the pro-inflammatory cytokine interleukin-1β (IL-1β) plays a key role in
initiating an immune response within the central nervous system (CNS).
The actions of IL-1β can be regulated by interleukin-1 receptor antagonist
(IL-1ra), which prevents IL-1β from acting on the IL-1type I receptor.
Consequently, the balance between IL-1ra/IL-1β is of pathological
importance, and pharmacological strategies that tip the balance in favour of
IL-1ra may be of therapeutic benefit. Evidence is emerging to suggest that
the neurotransmitter noradrenaline elicits anti-inflammatory actions in the
CNS, and consequently may play an endogenous neuroprotective role.
Here we report that noradrenaline induces production of secreted IL-1ra
from primary rat mixed glial cells. This noradrenaline-induced increase in
IL-1ra production is mediated via β-adrenoceptor activation, and
downstream signaling via the cAMP-Protein Kinase A pathway. In addition
to increasing IL-1ra, noradrenaline increased expression of the IL-1type II
receptor; a decoy receptor that serves to sequester IL-1β. The ability
noradrenaline to induce IL-1type II receptor expression was also mediated
via β-adrenoceptor activation. Importantly, in parallel with its ability to
increase IL-1ra and IL-1type II receptor expression, noradrenaline
attenuated functional responsiveness to IL-1β in mixed glial cells.
Considering that the pivotal role played by IL-1β in neuroinflammation, the
ability of noradrenaline to negatively regulate the IL-1 system in glial cells
may of therapeutic relevance in neurodegenerative disorders where
inflammation contributes to pathology.
The author acknowledge grant support from Science Foundation Ireland
22.02
The systemic control of acute and chronic inflammation in the
brain
Campbell S, Mann D, Deacon R, Jiang Y, Pitossi F, G³¹biñski A,
Anthony DC
Experimental Neuropathology, Department of Pharmacology,
University of Oxford, Oxfordshire, OX1 3QT, UK.,
Acute brain injury induces NFkB-dependent early and transient
hepatic expression of chemokines, which amplify the injury response
and give rise to movement of leukocytes into the blood and,
subsequently, the brain and liver. We have now discovered that an
ongoing injury stimulus within the brain continues to drive the hepatic
chemokine response, which impacts both on behaviour and on CNS
integrity. We generated chronic IL-1β expression in rat brain by
adenoviral-mediated gene transfer, which resulted in chronic leukocyte
recruitment, axonal injury, and prolonged depression of spontaneous
behaviour. IL-1β could not be detected in circulating blood, but a
chronic systemic response was established, including extended
production of hepatic and circulating chemokines, leukocytosis, liver
damage, weight loss, decreased serum albumin, and marked liver
leukocyte recruitment. Similarly, we have also discovered that an
extended hepatic chemokine response is a feature of chronic immunemediated
(PLP-EAE) CNS disease; increased hepatic chemokine
expression accompanies the onset of clinical signs. Thus hepatic
chemokine synthesis is a feature of active chronic CNS disease and
provides an accessible target for the suppression of CNS
inflammation.
22.03
Modulating microglial activation in the brain of aged rats impacts on
synaptic function
Lynch M A
Trinity College Institute of Neuroscience, Trinity College, Dublin
It is now accepted that several neurodegenerative conditions are
associated with evidence of neuroinflammatory changes and, similarly,
inflammatory changes are evident in brains of animal models of
neurodegenerative diseases. Among the features of inflammation is an
increase in microglial activation and this is likely to account for the
increased expression of proinflammatory cytokines like interleukin-1β (IL-
1β) which has also been reported in these conditions. Both increased
microglial activation and increased expression of several proinflammatory
cytokines, coupled with decreased expression of anti-inflammatory
cytokines like IL-4, have been shown to accompany ageing and these
changes are associated with deficits in cognitive function. This deficit in
cognitive function is typified by a decrease in one form of synaptic plasticity,
long-term potentiation (LTP), which is restored when the age-related
increase in microglial activation is attenuated. We have established that
reversing the age-related decrease in hippocampal IL-4 concentration is a
key factor leading to restoration of LTP and have found that IL-4 may
mediate its effects by modulating interaction between neurons and
microglia. Evidence will be presented which indicates that IL-4 increases
expression of the glycoprotein, CD200, on neurons and that interaction of
CD200 with its cognate receptor, CD200R, which is expressed on
microglia, is an important factor in maintaining microglia in a quiescent
state. Significantly CD200 expression is decreased with age, but at least
some measures which attenuate the age-related microglial activation
increase IL-4 and subsequently increase CD200 expression.
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