Book of abstracts - British Neuroscience Association

21.01
GAD levels in cerebellar Purkinje cells, interneurons and deep
cerebellar neurons in autism: pathophysiological implications
Yip J, Soghomonian J-J, Blatt G J
Department of Anatomy and Neuobiology, Boston University School of
Medicine, Boston, MA 02118 USA,
Purkinje cell loss is one of the most consistent findings in autism
neuropathology but little is known about their functional status.
Purkinje cells are the output neurons from the cerebellar cortex
sending inhibitory GABAergic projections to the cerebellar nuclei that
connect to the thalamus and higher association cortices. Purkinje cell
outputs are crucial for sensorimotor and cognitive functions. Purkinje
cells are vulnerable due to high metabolic demand, but the status of
GABAergic functions in the remaining PCs in the autistic brain remains
to be elucidated. In the current study, we used in situ hybridization
tecnhniques to investigate the mRNA levels of two isoforms of GABA
key synthesizing enzymes, glutamic acid decarboxylase (GAD)
GAD67 and GAD65. We demonstrated a 40% reduction in GAD67
mRNA levels Purkinje cells and a 28% increase in cerebellar basket
cells in the autistic cerebellar posterolateral lobe, a region previously
demonstrated to have the most robust Purkinje cells decrease. The
levels of GAD65 mRNA in the dentate nuclei were significantly
reduced, indicating potential adverse effects in their output projections
to higher centers. These results suggest that there is a deficit in
GABAergic function that may have contributed to the decreased
Purkinje cell numbers in autism. Reduced GABA transmitter release
from Purkinje cells in autism is likely to enhance neuronal excitability
consequently resulting in widespread changes to motor and/ cognitive
output from higher cortical centers in autism. Tissue was provided by
the Autism Research Foundation (TARF) and The Autism Tissue
Program. Supported by NICHD HD39459-04 (GJB, P.I.).
21.02
Neurochemical alterations in the autistic cerebellum: a model of
cerebellar dysfunction of the GABA/glutamate systems
Blatt G J, Yip J, Thevarkunnel S
Department of Anatomy and Neurobiology, Boston University School of
Medicine, Boston, MA 02118 USA
In the normal human cerebellar cortex, olivocerebellar climbing fibers
(OCFs) innervate up to ten Purkinje cells (PCs) and each PC receives a
single OCF input. In autism, a neurologic disorder characterized by delayed
and disordered language, stereotypical repetitive behavior and abnormal
socio-emotional interactions, many OCFs are abnormally thicker in caliber
width than age-matched adult controls, and some PCs receive multiple
OCF inputs. This suggests possible increased glutamate/aspartate
stimulation of PCs that potentially triggers off a cascade of neurochemical
and neurophysiological events that could adversely affect cerebellar output
via the deep cerebellar nuclei. Consequently, there is a down regulation of
AMPA receptors in the autistic cerebellar cortex that may also be the result
of abnormal mossy or parallel fiber innervation. Increased GAD67 in basket
cells (see Yip et al. abstract) may translate to increased GABA innervation
to PCs, and to support this, there is also a down regulation of GABA-A
receptors and benzodiazepine binding sites in the cerebellar cortex of adult
autistic subjects. These cerebellar cortical changes may directly affect the
functioning of the deep cerebellar nuclei leading to abnormal regulation of
high order cortical association areas that participate in the motor and/or
cognitive behaviors associated with autism. Tissue was provided by the
Autism Tissue Program (ATP) and The Autism Tissue Foundation (TARF).
Grant support was provided by NIH NICHD HD39459, Cure Autism Now
Foundation, the Institute for Brain Potential and the Hussman Foundation
(all GB, P.I).
21.03
Cholinergic systems in autism
Perry E, Maddick M, Court J
Cholinergic systems may be involved in attentional dysfunction in
autism. Our previous autopsy investigations indicated nicotinic and
muscarinic acetylcholine receptor deficits in some brain areas in young
adults with autism. Major reductions ( 50-70%) in α4β2 containing
nicotinic receptors were evident in the neocortex and cerebellum,
whereas less severe deficits were observed in muscarinic receptors
(M1, 30% in parietal cortex).
Anatomically, nicotinic receptor deficits were extensive, being evident
in many neocortical regions (BA 7, 9, 17 and 39), the thalamus and
striatum as well as cerebellum. A consistent and significant reduction
in M1 receptors was also demonstrated in the striatum but not the
thalamus.
Since the cholinergic system may have a role in neurogenesis and the
establishment of cytoarchitecture during brain development, we
examined cholinergic markers (choline acetyltransferase activity,
muscarinic M1 receptors and α4β2 containing receptor binding in
children with autism (2-9 years). In contrast to the adult, high affinity
nicotinic receptor binding (α4β2) was not reduced in the frontal cortex
of children with autism. There were also no significant changes in α-
bungarotoxin (α7) or pirenzepine (M1) binding in this brain region.
However a proportion of children with autism in common with some
adults exhibited very low M1 receptor binding in the frontal cortex
suggestive of this being a feature in a subset of autistic individuals.
Since the earlier pathological studies, pilot clinical trials have indicated
the possible benefit of cholinergic therapy in both adults and children
with autism.
21.04
Glial cells within the cerebral cortex in autism
Rezaie P, Landau S, Mason S, Schmitz C
Neuropathology Research Laboratory, Department of Biological Sciences,
The Open University, Milton Keynes MK7 6AA, and Department of
Neuroscience, Institute of Psychiatry, King’s College London, DecRespigny
Park, London SE5 8AF
The underlying neurobiology of autism remains obscure. However, subtle
disturbances in the development of neurons within the brain, and certain
immune system abnormalities are believed to occur in patients with autism.
Neuro-immune interactions are governed locally by networks of resident
glial cells- microglia and astrocytes, whose activation parallels ongoing
pathology within this tissue. Disturbances in the function of glial cells may
have adverse consequences on the activity of neurons and vice versa.
Neuroglial activation and neuroinflammation have been proposed to
contribute towards the neuropathology of autism. Previously, we reported
differential activation of microglia and astrocytes within the frontal lobe of a
cohort of cases with autism (Neuropathol. Appl. Neurobiol. 2006; 32:226-
227) - glial cell activation was largely restricted to astrocytes within cortical
white matter (WM) in all autism cases examined. Considering that such WM
astrocyte activation was not associated with diffuse axonal injury, postmortem
delay, age or history of seizures in autism, and taken together with
the lack of lymphocytic/monocytic infiltration, or of significant microglial
activation, we proposed that glial cell alterations do not necessarily reflect
‘neuroinflammation’ as recently suggested. Instead they may be a
consequence of acute hypoxic-ischaemic injury associated with the agonal
state of the cases examined, or they could represent a specific dysfunction
targeting astrocytes in autism. We have now systematically investigated
glial cell responses within several regions of the cerebral cortex known to
be affected in autism, in a separate cohort of cases derived from the Autism
Tissue Program (USA).
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