Book of abstracts - British Neuroscience Association

46.01
Neurotransmitter regulation of the sleep-waking cycle
Haas H L
Institute of Neurophysiology, Heinrich-Heine-University, Düsseldorf,
Germany
Sleeping, waking, feeding and resting at the right time in the right
place is an advantage in Darwin’s sense. Our biological clock is
synchronized by light and creates signals for the daily rhythm which is
modulated by homoeostatic sleep pressure factors such as adenosine.
The ascending arousal system comprises cholinergic, serotonergic,
noradrenergic and dopaminergic cell groups in the brain stem as well
as histaminergic neurons located in the posterior hypothalamus
(tuberomamillary nucleus) and orexin/hypocretin - containing neurons
in the nearby perifornical area. The two latter major waking centers
project widely through the whole brain and are tonically active during
wakefulness but cease firing during sleep. Are the aminergic neurones
playing in a self-organizing orchestra or under a conductor like the
orexin nucleus They are all switched off through GABAergic inhibition
from the sleep active preoptic area. The orexin neurones integrate
circadian, metabolic and feeding signals and control the transitions
between slow wave sleep, REM sleep and waking. Degeneration of
these neurons results in a severe disorder of sleep architecture, called
narcolepsy with diurnal sleep attacks, inadequate transitions to a
REM-sleep like state, cataplexy, with loss of muscle tone, not
consciousness, out of the waking. Hypnagogig hallucinations, dreams
before the loss of consiousness occur at sleep onset. The orexin
neurones provide “flip-flop switches” (C. Saper) that prevent too
frequent oscillations between the sleep and waking states.
46.02
Mechanisms of general anaesthesia and the involvement of sleep
pathways
Franks N P
Biophysics Section, Blackett Laboratory, Imperial College of Science,
Technology and Medicine, South Kensington, London SW7 2AZ, U.K
Because the potencies of most anaesthetics can be accurately predicted by
lipid partitioning (the Meyer-Overton correlation), they have long been
considered to be archetypal “non-specific” drugs. However, this view has
now changed radically and it is recognised that even the simplest
anaesthetics (including the inert gas xenon) can be surprisingly selective in
their actions and exert their effects by binding directly to protein targets.
Identifying which protein targets are pharmacologically relevant, and which
are not, has been a major challenge, yet great progress has been made in
recent years. In this talk I will review the evidence on the nature and identity
of anaesthetic binding sites in the central nervous system and show that for
some commonly used agents, the relevant targets can be unambiguously
identified. The identification of the important anaesthetic targets has
facilitated investigations into the possible connections between the
mechanisms underlying general anaesthesia and those responsible for
natural sleep. Because the one behavioural feature that is common to all
general anaesthetics is their ability to induce a loss of consciousness that,
at least superficially, resembles natural non-REM sleep, it has long been
suspected that the neuronal pathways that are involved in NREM sleep
may also be relevant to the induction and maintenance of general
anaesthesia. Only recently, however, has evidence showing a causal link
been provided. I will describe experiments that show how certain key nuclei
in the brain, which are involved in the regulation of sleep, are also involved
in the sedative actions of general anaesthetics.
47.01
Synaptic function of the synaptic vesicle-associated CSP/Hsc70
chaperone
Zinsmaier K E
Arizona Research Laboratories Division of Neurobiology, Department
of Molecular and Cellular Biology, University of Arizona, Tucson, AZ
85721.
Synaptic terminals exhibit not only a remarkable speed and precision
as secretory machines but also an autonomy and durability that is
unusual. Not surprisingly, synaptic terminals contain special
mechanisms that protect them from detrimental effects of damaged,
aged or otherwise functionally impaired proteins. Accumulating
evidence suggests that molecular chaperones facilitate numerous
synaptic mechanisms and form a critical first line of defense against
diverse neurodegenerative diseases that might have a common cause
— the misfolding, aggregation and accumulation of toxic protein forms
in the brain. Genetic studies in flies and mice suggest that the synaptic
vesicle-associated cysteine string protein (CSP) is a key factor for the
maintenance of synaptic function. Specifically, our genetic studies
support four roles for CSP at synaptic terminals of Drosophila NMJs:
1) CSP protects synapses against use- and/or stress-induced damage
and prevents subsequent degeneration of nerve terminals. 2) CSP
facilitates a step close to SNARE-mediated synaptic vesicle fusion. 3)
CSP facilitates presynaptic Ca2+ homeostasis and may control Ca2+
channel activities. 4) CSP facilitates synaptic growth. The protective
role of CSP is at least in part based on its biochemical function as a
cofactor of the classical chaperone heat-shock cognate protein
(Hsc70). I will further discuss whether the cooperative synaptic action
of CSP and Hsc70 requires small glutamine-rich tetratricopeptide
repeat-containing protein (SGT).
47.02
Targeting cellular prion protein reverses early cognitive deficits and
neurophysiological dysfunction in prion-infected mice.
Mallucci GR 1, White MD 1, Farmer M 1, Dickinson A 1, Khatun H 2, Powell
AD 2, Brandner S 1, Jefferys JGR 2, Collinge J 1
1MRC Prion Unit and Department of Neurodegenerative Disease, Institute
of Neurology, Queen Square, London WC1N 3BG, UK
2Department of Neurophysiology, Division of Neuroscience, University of
Birmingham, Birmingham, B15 2TT.
Currently no treatment can prevent the cognitive and motor decline
associated with widespread neurodegeneration in prion disease. However,
we previously showed that targeting endogenous neuronal prion protein
(PrPC) (the precursor of its disease-associated isoform, PrPSc) in mice
with early prion infection, reversed spongiform change and prevented
clinical symptoms and neuronal loss. We now show that cognitive and
behavioral deficits and impaired neurophysiological function accompany
early hippocampal spongiform pathology. Remarkably, these behavioral
and synaptic impairments recover when neuronal PrPC is depleted, in
parallel with reversal of spongiosis. Thus early functional impairments
precede neuronal loss in prion disease and can be rescued. Further, they
occur before extensive PrPSc deposits accumulate and recover rapidly
after PrPC depletion, supporting the concept that they are caused by a
transient neurotoxic species, distinct from aggregated PrPSc. These data
suggest that early intervention in human prion disease may lead to
recovery of cognitive and behavioral symptoms.
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