Contact us:
Yan-Fang
Xia
Research
Subjects:
Cellular and
molecular
pharmacology of AMPA receptors
Most excitatory synaptic transmission in
the
brain is mediated through AMPA-type glutamate receptors and thus
changes
in the properties of these receptors are likely to have considerable
impact
on brain function. The main focus of our laboratory is on endogenous
mechanisms
and drugs which alter the kinetic properties of AMPA receptors and on
the
consequences of such receptor modulation for synaptic transmission and
local network properties.
organotypic slice culture
Department
of Pharmacology
SIU School of Medicine
P.O.Box
19629
Springfield
IL 62794-9629
or
Department
of Pharmacology
SIU
School of Medicine
Room 3321 (office)
or Room 3275 (laboratory)
Mail
code 9629
801
N. Rutledge Street
Springfield
IL 62702
Tel:
217-545-2204 (Laboratory)
Tel:
217-545-0228 (Arai Office)
FAX:
217-545-0145
New publication
:
Arai AC, Xia Y-F, Suzuki E, Kessler M, Civelli O,
Nothacker H-P. (2005) The cancer metastasis suppressing peptide
metastin upregulates excitatory synaptic transmission in hippocampal
dentate granule cells. J.
Neurophysiol, 94: 3648-3652.
Kessler M, Arai AC (2006) Use of [3H]fluorowillardiine to study properties of AMPA allosteric modulators. Brain Res. 1076: 25-41.
Xia Y-F, Arai AC
(2005) AMPA receptor modulators have different impact on hippocampal
pyramidal cells and interneurons. Neuroscience 135: 555-567.
Suzuki E, Kessler M, Arai AC (2005) C-terminal
truncation affects kinetic properties of GluR1 receptors.
Mol Cell Neurosci. 29:
1-10.
Xia Y-F, Kessler
M, Arai AC (2005) Positive AMPA receptor modulators have
differential
impact on synaptic transmission in the thalamus and hippocampus. J.
Pharmacol. Exp. Ther.,
313: 277-285.
Suzuki E, Kessler
M, Montgomery K, Arai AC (2004) Divergent
effects
of the purinoceptor antagonists suramin and PPNDS on AMPA receptors. Mol.
Pharmacol. 66:1738-1747.
Arai AC, Xia
Y-F, Suzuki
E (2004) Modulation of AMPA receptor kinetics differentially
influences
formation of synaptic plasticity in the hippocampus. Neuroscience
123: 1011-1024.
Effects of AMPA receptor modulators on receptor kinetics, ligand binding, synaptic transmission, and synaptic plasticity:
1-BCP
CX516
(BDP-12)
BDP-20 (CX554)
CX546
CX614
IDRA-21
D-1
cyclothiazide
GYKI
aniracetam
thiocyanate
suramin/PPNDS
Links:
Sangamon
Chapter Society for Neuroscience
National
Pediatrics Myoclonus Center
AMPA receptor
modulators
AMPA receptor modulators are compounds
which
potentiate the effects of the endogenous transmitter glutamate. Earlier
collaborations with chemists resulted in numerous such compounds,
called
Ampakines. We have shown that selective enhancement of AMPA receptors
by
these drugs facilitates the formation of long-term potentiation (LTP),
a cellular mechanism believed to be responsible for memory encoding.
Others
have shown that these compounds, as predicted, improve many types of
memory
in animal tests. Some of these compounds are currently examined
in
clinical trials for their use against Alzheimer's disease and
schizophrenia.
On our part, we continue investigating how different subtypes of these
modulators influence AMPA receptor kinetics, synaptic transmission, and
synaptic plasticity.
Synaptic
plasticity
Hippocampal
interneurons
Thalamic
synaptic transmission
Calpain
& Ischemia
Multielectrode
recording
Cerebellum
RF-amide
Peptide Receptors
Positive Modulation of AMPA
Receptors:
Effects on Synaptic Transmission, Plasticity and Networks
AMPA receptor function differs across brain
regions,
mainly due to variation in subunit composition, but also because of
differences
in the characteristics of synapses and local circuits. Depending
on such properties, AMPA receptor mediated synaptic currents may be
sharp
or slow, may or may not be associated with calcium influx, and may
exhibit
either paired-pulse facilitation or paired-pulse depression, and there
is much evidence that these differences are relevant for brain function
and ultimately for behavior. The AMPA receptor modulators described
above
are a novel and enormously useful tool with which we can examine many
aspects
of this diversity in AMPA receptor mediated signaling. We are currently
conducting such studies in which we compare properties of synaptic
transmission
between hippocampus, thalamus and inferior colliculus, and among cell
types
within these structures, using whole-cell recording in brain slices.
Kinetic Properties of AMPA
Receptors
The kinetic properties of AMPA receptors
evidently
are critical for determining the waveform of synaptic currents, but the
relationship between them is not yet entirely clear. There is also
evidence
that AMPA receptors may exist in different ‘affinity states’ and that
homomeric
recombinant receptors differ from brain receptors. One of our main
goals
is to compare kinetic properties of recombinant receptors with those
measured
in native AMPA receptors in synapses and in membrane patches excised
from
hippocampal slices, and to integrate kinetic data from physiological
recordings
with those from ligand binding assays. Experimental data are then
compared
with simulations using kinetic receptor models.
Paired application of 1-ms pulses to the AMPA receptor in a membrane patch excised from a pyramidal cell in the hippocampal CA1 field. The amplitude of the second response is reduced because of receptor desensitization.
Receptors for Prolactin-releasing
peptide
(PrRP) Regulate Thalamic Function
The prolactin-releasing peptide (PrRP)
receptor
is highly expressed in the reticular nucleus of the thalamus (RNT), but
its role in the function of this brain region is not yet
understood.
The RNT controls the flow of information from the senses through the
thalamic
nuclei to the cortex and it is believed to be important, for instance,
for regulating sleep and attention. In a recent study we have shown
that
application of PrRP to thalamic slices suppresses oscillatory activity
that resembles the slow-wave discharges seen during sleep, and that
i.c.v.
injection of this peptide reduces EEG seizures in an animal model for
absence
seizures. This suggests that drugs acting on this receptor may some day
be of use to control various thalamic functions and the associated
disorders.
Currently, our main interest is to investigate how PrRP receptors
influence
the physiology of the principal neurons in the RNT, and which
intracellular
signaling pathways are activated by the PrRP receptor.
Prolactin-releasing
peptide (PrRP) receptor
hippocampal neuron grown on a microisland
MAP (green) and synapsin (red)
Search for autoantibodies
associated
with paraneoplastic neurological disorders
Children with neuroblastoma sometimes
experience
motor problems characterized by dancing eye movement and difficulty in
keeping the posture. The symptoms are not caused by the neuroblastoma
itself
but rather by autoantibodies or other factors released in response to
the
tumor, and hence the disorder is described as 'paraneoplastic
neurological
syndrome'. In a collaboration with Michael Pranzatelli, M.D.,
Director
of the National Pediatric Myloclonus Center, we are searching for
autoantibodies
that might impair the function of the cerebellum, the brain region that
is likely to be the source for the abnormal movements. For this we are
using a novel approach in which the patient serum is applied to tissue
cultures of rat cerebellum that are grown on a special dish containing
an array of 64 electrodes. This system allows us to record evoked
and spontaneous electrical activity over days to weeks and to examine
if
autoantibodies present in the serum cause a progressive impairment of
this
activity.
cultured cerebellar slice on
multi-electrode dish (MED)
Long-term changes in hippocampal
physiology
after ischemia: in vitro studies using cultures grown on a
8x8-electrode
array.
Transient hypoxia/ischemia can lead to
delayed
neuronal degeneration days after the insult. Processes involved in such
degeneration have until now been mainly studied with biochemical
methods.
The recent development of culture dishes with embedded electrode array
now makes it possible for the first time to look in an in vitro
preparation for long-term physiological changes that may be involved in
neuronal degeneration. Using this system, we currently examine if the
function
of AMPA receptors and other glutamate receptors changes after ischemia
and if such changes can be controlled by applying specific inhibitors
of
proteases or various intracellular signaling mechanisms.
cultured hippocampal slice on MED
