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First published online May 26, 2006
Journal of Experimental Biology 209, 2293-2303 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.01985
Review Article: Phenotypic Plasticity of the Brain |
Comparative plasticity of brain synapses in inbred mouse strains
Laboratory of Synaptic Plasticity, Department of Physiology and Centre for Neuroscience, University of Alberta School of Medicine, Medical Sciences Building, Edmonton, T6G 2H7, Canada
e-mail: Peter.Nguyen{at}ualberta.ca
Accepted 14 November 2005
Summary
One niche of experimental biology that has experienced considerable progress is the neurobiology of learning and memory. A key contributor to such progress has been the widespread use of transgenic and `knockout' mice to elucidate the mechanisms of identifiable phenotypes of learning and memory. Inbred mouse strains are needed to generate genetically modified mice. However, genetic variations between inbred strains can confound the interpretation of cellular neurophysiological phenotypes of mutant mice. It is known that altered physiological strength of synaptic transmission (`synaptic plasticity') can modify and regulate learning and memory. Characterization of the synaptic phenotypes of inbred mouse strains is needed to identify the most appropriate strains to use for generating mutant mouse models of memory function. More importantly, comparative electrophysiological analyses of inbred mice per se can also shed light on which forms of synaptic plasticity underlie particular types of learning and memory. Many such analyses have focused on synaptic plasticity in the hippocampus because of the critical roles of this brain structure in the formation and consolidation of long-term memories. Comparative electrophysiological data obtained from several inbred mouse strains are reviewed here to highlight the following key notions: (1) synaptic plasticity is influenced by the genetic backgrounds of inbred mice; (2) the plasticity of hippocampal synapses in inbred mice is `tuned' to particular temporal patterns of activity; (3) long-term potentiation, but not long-term depression, is a cellular correlate of behavioural memory performance in some strains; (4) synaptic phenotyping of inbred mouse strains can identify cellular models of memory impairment that can be used to elucidate mechanisms that may cause specific memory deficits.
Key words: synaptic plasticity, hippocampus, inbred mice, mouse strain, long-term potentiation (LTP), long-term depression (LTD), learning, memory
Introduction
All of experimental biology is, in one way or another, aimed at identifying and characterizing the mechanisms that produce identifiable phenotypes in cells, tissues and organisms. This is especially true of neuroscience research. At multiple levels of experimental analysis, the diversity of behavioural, neurophysiological and neurochemical phenotypes seen in mammals is, in large part, a result of the complexity of numerous brain functions. These functions include cognitive processes such as learning, memory and perception, and cellular actions such as activity-dependent modifications of synaptic strength (`synaptic plasticity').
Understanding the mechanisms of synaptic plasticity and memory is an
important goal of neuroscience. Murine transgenic and gene-targeting
techniques are invaluable methods for elucidating the roles of genes and
intracellular signalling pathways in synaptic plasticity and memory
(Wehner et al., 1996
;
Picciotto and Wickman, 1998;
Micheau and Riedel, 1999;
Martin et al., 2000). Within
specific brain regions, single genes may be artificially overexpressed
(Jaenisch and Mintz, 1974;
Constantini and Lacy, 1981;
Palmiter et al., 1982;
Mayford et al., 1996), or
their expression may be reduced or eliminated by targeted mutagenesis
(Thomas and Capecchi, 1986;
Bradley, 1993). These molecular
strategies have been effectively applied to generate genetically modified mice
for mechanistic investigations of synaptic plasticity and memory
(Picciotto and Wickman,
1998).
Two inbred strains of mice are commonly used to generate genetically
modified mice. An inbred strain is one in which matings between siblings have
been performed for at least 20 generations, resulting in a population of
genetically homogeneous animals (Lyon and
Searle, 1989). One inbred strain supplies a viable genetic
background for breeding and survival, whereas a second inbred strain provides
stem cells for genetic manipulation (Hogan
et al., 1994). An important consideration inherent in all of these
studies is that disruption or overexpression of a single gene can lead to
compensatory changes in the expression of other genes, the presence or absence
of which can vary according to the genetic backgrounds of the mouse strains
used to generate a genetically modified line of mice
(Crawley et al., 1997). Valid
interpretation of the neurophysiological phenotypes that emerge from
genetically modified mice therefore requires knowledge of the synaptic
properties of relevant neurons in the parent strains used to produce
genetically modified lines of mice. Hence, the characterization of synaptic
phenotypes of neurons in relevant brain structures of inbred mice is an
important step towards defining the genetic and molecular bases of synaptic
plasticity. It can also lead to the compilation of physiological databases
(mouse `physiomes') needed to construct mouse models of synaptic and cognitive
dysfunction.
Long-term potentiation (LTP) and long-term depression (LTD) constitute
activity-dependent enhancement and reduction, respectively, of excitatory
synaptic strength (Lomo, 1966;
Bliss and Lomo, 1973;
Dudek and Bear, 1992). These
two types of synaptic plasticity are believed to play important roles in
mediating learning and memory (Martin et
al., 2000; Lynch,
2004), perception (Klein et
al., 2004), and the refinement of synaptic circuitry
(Kirkwood et al., 1995). In
humans and mice, area CA1 (cornu ammonis-1) of the hippocampus is vital for
the formation of long-term memory
(Zola-Morgan et al., 1986;
Tsien et al., 1996). Genetic
modifications of key signalling molecules within area CA1 of the mouse
hippocampus can impair long-term memory and LTP (reviewed by
Lynch, 2004). Some comparative
data showing strain-associated variations of hippocampal memory and
LTP in area CA1 of in vitro slices have been reported
(Nguyen et al., 2000a;
Nguyen et al., 2000b;
Schimanski et al., 2002;
Schimanski et al., 2005a; Schimanski et al., 2005b) [for in vivo
data, see (Bampton et al.,
1999; Jones et al.,
2001)]. However, the mechanisms underlying strain-dependent
variations in LTP are mostly undefined, and conjoint characterization of LTP
and memory in inbred mouse strains is still nascent. Also, it should be
emphasized that comparative analysis of inbred strains can shed light on which
particular types of synaptic plasticity are critical for expression of
specific forms of learning and memory. The question, `Does LTP=memory?' can be
effectively addressed by using inbred mice: they provide an experiment of
nature to test this hypothesis in a less biased manner than experiments that
use reverse genetic approaches.
One of the goals of this article is to provide newcomers to this field with
information to `get started' with phenotyping of hippocampal synapses in mouse
strains. A second goal is to provide a succinct, selective overview of
comparative in vitro synaptology of inbred mice. Some in
vitro electrophysiological methods for probing hippocampal synaptic
plasticity are described, along with comparative data from selected inbred
mouse strains. Brief coverage of memory function is provided to underscore the
notion that some types of behavioural memory can be correlated with particular
forms of synaptic plasticity in inbred strains. Readers seeking more in-depth
coverage of memory functions in mice, and quantitative genetics of mouse
behaviour, should consult additional sources
(Crawley, 2000;
Wehner et al., 2001;
Wahlsten et al., 2003;
Greenspan, 2004;
Schimanski and Nguyen,
2004).
Methods for assessing synaptic plasticity in mouse hippocampal slices
C57BL/6J (`B6') is frequently used as a `background' strain for breeding
congenic and transgenic mice, and as a `control' for inter-strain comparisons
of synaptic plasticity, learning and memory. Mice of various strains, aged
8–13 weeks, were used for most of the experiments reviewed here
(Nguyen et al., 2000a;
Nguyen et al., 2000b;
Schimanski and Nguyen, 2005a;
Schimanski and Nguyen,
2005b).
Many aspects of the methods described below are used in several
laboratories (e.g. Nayak et al.,
1998; Bozdagi et al.,
2000; Matsushita et al.,
2001; Knapp and Klann,
2002; Vanhoose and Winder,
2003; Ferguson et al.,
2004; Ho et al.,
2004; Sajikumar et al.,
2005; Wood et al.,
2005; Young and Nguyen,
2005). There are variations in these methods. These usually
pertain to the type of slice chamber used (interface versus
submerged), the temperature at which slices are maintained, and the
stimulation protocols used to induce synaptic plasticity. I describe
extracellular methods only, because they are relatively simple to learn (and
thus, are used extensively) and they can provide stable recordings of synaptic
potentials over several hours of experimentation. I also present some
whole-cell patch clamp data; methods for single-cell patch clamp recording are
described elsewhere (Nguyen et al.,
2000b).
Hippocampal slice preparation and interface slice chambers
Mice are sacrificed by rapid cervical dislocation followed by decapitation.
The isolated brain (Fig. 1A) is
transferred to a beaker of ice-cold artificial cerebrospinal fluid (ACSF;
composition in mmol l–1: 124 NaCl, 4.4 KCl, 1.3
MgSO4, 1.0 NaH2PO4, 26.2 NaHCO3,
2.5 CaCl2, 10 glucose). It is important that all ACSF used during
the dissection is bubbled with a mixture of 95% O2 and 5%
CO2. This `carbogen' mixture is needed to maintain proper pH
balance of the bicarbonate-buffered ACSF. The hippocampus is isolated from the
adjoining brain hemisphere and is placed on an acrylic platform lined with a
piece of filter paper. Once oriented with its longitudinal axis perpendicular
to a razor blade that is mounted on a manual tissue chopper (Stoelting,
Woodale, IL, USA), the hippocampus is cut into 400 µm-thick slices. A drop
of ACSF is applied to the isolated whole hippocampus immediately prior to
sectioning so that slices can adhere to the blade. A fine paintbrush is used
to gently transfer slices from the blade to a small glass Petri dish
containing ice-cold oxygenated ACSF.
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An interface chamber allows maintenance of partially submerged, physiologically viable brain slices at pre-set temperatures within a humidified environment. Many labs maintain slices at temperatures ranging from room temperature up to 34°C. Generally, with an interface chamber, higher temperatures tend to increase the rate of moisture condensation on the surfaces of glass recording electrodes. This condensation can drop onto slices during an experiment. When this occurs, field EPSP recordings can be obliterated. One solution to this problem is to use a fine thread or strand of facial tissue to gently wipe away small drops of condensation on the electrode shank during experiments. Also, rubbing dental wax onto the shanks of glass microelectrodes can provide an absorbent surface that reduces the amount of free condensation formed on these electrodes.
After a recovery period of at least 1 h, extracellular field excitatory
postsynaptic potentials (fEPSPs) are recorded with an ACSF-filled glass
microelectrode (see below) positioned in the stratum radiatum of area CA1.
These fEPSPs represent the collective synaptic responses generated by
activation of populations of postsynaptic CA1 neurons. Evoked fEPSPs are
elicited by stimulation of Schaeffer collateral fibres
(Schaeffer, 1892) using an
extracellular bipolar nickel–chromium electrode (see below). These
fibres provide synapses that excite the apical dendrites of CA1 pyramidal
neurons. Substantial information on synaptic transmission has been derived
from studies of these synapses; they are prototypical chemical synapses in the
mammalian central nervous system.
Electrodes and data analysis
Bipolar stimulating electrodes are created by twisting two fine nickel
chromium wires (A-M Systems, Carlsborg, WA, USA) together and sealing them
within a glass capillary tube. Because the thin wires are coated with formvar,
one end of the wires is briefly flamed to strip away the coating, and then the
stripped segment is connected via an isolator to a stimulator (e.g.
Grass Instruments model S88, West Warwick, RI, USA). The final diameter of the
stimulation electrode is approximately 130 µm. After repeated usage over
several weeks, a noticeable increase in the threshold for eliciting fEPSPs
usually occurs. A razor blade is then used to trim off the distal tip of wires
in order to obtain a new electrode surface for tissue stimulation. With daily
usage, this process is generally required every 2–4 weeks. At the end of
each day's experiments, the distal tip of the electrode that had contacted
brain tissue should be cleaned by brief immersion in ethanol followed by
distilled water. This procedure appears to decrease the frequency of electrode
trimming required to `refresh' these electrodes.
Glass recording electrodes are produced from a micropipette puller (e.g.
Flaming Brown P-87 puller, Sutter Instruments, Novato, CA, USA). The recording
electrode can be filled with ACSF and it should have an electrical resistance
of 1–3 M
.
The stimulation intensity (0.08 ms pulse width) is adjusted to give fEPSP amplitudes that are approximately 40% of maximal fEPSP sizes. Control `baseline' responses are elicited once per minute at this intensity. Slices that show maximal fEPSP sizes smaller than 3 mV are rejected.
For two-pathway experiments, two stimulating electrodes (S1 and S2) are placed in the stratum radiatum on opposite sides of the recording electrode to stimulate two separate groups of Schaeffer collateral fibres. The independence of the two pathways is demonstrated by the absence of paired-pulse facilitation of fEPSPs when two successive stimuli are delivered to the two pathways at a 50 ms interpulse interval.
|
Stimulation protocols
LTP is induced by applying one of several different protocols, including a
single 1 s train of 100 Hz (henceforth referred to as `single-train'), four 1
s trains of 100 Hz (henceforth referred to as `multi-train') spaced at various
intervals, or theta-burst stimulation. A theta-burst stimulation protocol can
consist of 15 bursts of four pulses each, delivered at a pulse frequency of
100 Hz with a 200 ms interburst interval. These protocols are used because
they induce distinct forms of LTP that have been correlated with particular
types of hippocampus-dependent memory. In mouse hippocampal slices, a
single-train stimulus induces `early' LTP (E-LTP) that is strongly correlated
with hippocampus-dependent short-term memory for contextual fear conditioning
(Abel et al., 1997), whereas
multi-train stimulation induces a long-lasting, `late' phase of LTP (L-LTP,
Fig. 2A) that is correlated
with hippocampal long-term memory (Abel et
al., 1997). L-LTP, but not E-LTP, requires translation and
transcription (Fig. 2B)
(reviewed by Nguyen and Woo,
2003). Theta-burst stimulation mimics hippocampal spike discharge
patterns that occur during some types of exploratory behaviour in rodents
(Larson et al., 1986;
Otto et al., 1991).
The converse of LTP, long-term depression (LTD), can be induced by giving 1 Hz stimulation for 15 min to slices cut from mice aged 4–5 weeks.
Strain-related variations in hippocampal LTP and LTD: mechanisms and insights
Comparative studies of hippocampal memory in several inbred mouse strains
have demonstrated strain-dependent variations of hippocampal memory expression
(Paylor et al., 1993;
Paylor et al., 1994). These
studies prompted conjoint analyses of hippocampal memory and hippocampal
synaptic plasticity in area CA1 of these strains
(Nguyen et al., 2000a), as
well as detailed investigation of the cellular bases for strain-related
deficits in CA1 LTP (Nguyen et al.,
2000b). These investigations focused on four inbred strains:
C57BL/6J (`B6'), CBA/J (`CBA'), DBA/2J (`DBA') and 129/SvEms/J (`129'). These
were selected because they have been used to generate mutant mice for
neurobiological research, and therefore, the phenotypes of these parental
strains should be of broad interest to neuroscientists. The objective of these
studies was to identify cellular correlates of the memory deficits seen in
some of these strains. Collectively, these studies produced the following
observations and conclusions:
;
Nguyen et al., 2000b).
Hippocampal slices from CBA, 129 and DBA mice showed less robust induction and
maintenance of LTP than B6 slices following multi-train
(Fig. 3) or theta-burst
stimulation. Hence, defective LTP in mutant mice generated from these strains
may result from the genetic background of the parent strain rather than from
the genetic manipulation per se. ). LTP
was enhanced in slices from strain 129 following repeated stimulation using 3
s interburst intervals (Fig.
4), whereas the same total amount of imposed activity produced
less robust LTP when a 20 s interburst interval was applied
(Fig. 3). In slices from CBA,
DBA and B6 mice, changing the interburst interval from 20 s to 3 s, while
keeping the total imposed activity constant, did not significantly affect LTP
(Nguyen et al., 2000b).
However, changing interburst intervals had opposite effects on maintenance of
LTP in 129 and DBA slices: in 129, decreasing the interburst interval
increased LTP (Fig. 3A,
Fig. 4A), whereas in DBA,
decreasing the interval reduced LTP (Fig.
3B, Fig. 4B). In
other words, the hippocampal neurons of some inbred mouse strains are more
`tuned' to particular temporal patterns of synaptic activity because of
strain-related variations in genetic background. These findings also emphasize
the importance of using various temporal patterns of synaptic stimulation to
probe for altered synaptic plasticity. ). There
were no significant strain-specific differences in membrane input resistance,
spike frequency accommodation, and membrane depolarization (during 100 Hz
stimulation) in CA1 pyramidal cells from these strains. Thus, genetic
variation among these four strains did not significantly alter membrane
biophysical properties or spiking efficacy of CA1 neurons. ), which
showed that, for some inbred and hybrid strains (129/Sv, 129/SvXC57BL/6 and
129 SvXCD1), LTP of AMPA- and NMDA-type currents was independent of genetic
background. Thus, the genetic backgrounds of many inbred mouse strains do not
significantly alter the amplitudes of synaptically evoked glutamatergic
currents. ). DBA and CBA mice displayed deficits in both
hippocampus-dependent spatial memory and fear conditioning
(Nguyen et al., 2000a), but
they showed intact LTD (Nguyen et al.,
2000b). Thus, LTP, but not LTD, may be a cellular mechanism for
hippocampal memory in these strains.
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Variations in hippocampal LTP are certainly not confined to these four
inbred strains. Other inbred mouse strains also display deficits in particular
forms of LTP in hippocampal and amygdalar circuits, as assessed using in
vitro techniques (Schimanski and
Nguyen, 2004; Schimanski and
Nguyen, 2005a; Schimanski and
Nguyen, 2005b). It should be noted that many studies using genetic
methods have reached similar conclusions, and that inducible systems, e.g.
doxycycline-mediated expression of transgenes
(Kistner et al., 1996) are
also effective means of addressing the question, `Does LTP=memory?'.
Hippocampal synaptic plasticity and memory function
Conjoint measurements of synaptic and mnemonic phenotypes have been
accomplished for several inbred mouse strains
(Table 1). These data
underscore the notion that it is difficult to make broadly based, generic
correlations between fear conditioning (a key memory task used in mouse
behavioural research) (see Crawley,
2000; Schimanski and Nguyen,
2004) and LTP. Some consistent correlations exist
(Table 1), but not every strain
tested has yielded data that would definitively establish generic correlations
between particular forms of LTP and fear conditioning. For example, some forms
of CA1 LTP are excellent cellular correlates of contextual fear memory in
many, but not all, strains that have been tested; one exception is strain
129/SvEms/J (Table 1). Also,
LTP in the medial perforant pathway (MPP) is not a good cellular correlate of
contextual fear memory, because in two strains, DBA/2J and C3H/HeJ, defective
memory is present alongside intact MPP-LTP. In order to generalize these
conclusions, more thorough examination of other inbred strains is
necessary.
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Synaptic phenotyping of inbred mice can shed light on the synaptic
mechanisms that contribute to information processing by specific subregions of
the mammalian hippocampus. Different computational functions, such as pattern
association and temporal pattern completion, may be mediated by distinct
hippocampal subregions (Kesner et al.,
2000). Synaptic plasticity in CA1 and the dentate gyrus may be
correlated with these functions, but this idea can only be rigorously tested
by combining detailed electrophysiological analysis with well-defined
behavioural tests that substantially target selected subregions of the
hippocampal formation. Such targeting has been accomplished at the molecular
level, using subregion-specific knockouts of key molecules, such as the NMDA
receptor in areas CA1 (Tsien et al.,
1996) and CA3 (Nakazawa et
al., 2002). These studies implicated critical roles in memory
processing and memory recall for these subregions of the hippocampus.
Additionally, other forms of activity induced synaptic plasticity might be
modified in inbred mice. For example, altered `metaplasticity', i.e.
plasticity of synaptic plasticity (Abraham
and Bear, 1996), of synapses might correlate with behavioural
performance on some memory tasks, such as extinction. In slices from B6 mice,
low-frequency stimulation that does not alter synaptic strength per
se can still suppress future L-LTP, but only when such stimulation is
given within a critical time window before L-LTP induction
(Fig. 6)
(Woo and Nguyen, 2002).
It is unclear whether other inbred strains would display similar anterograde
metaplasticity of L-LTP, but deficits in such metaplasticity might contribute
to the inability of some strains to form stable long-term memories (cf.
Abraham and Robins, 2005). If
deficits are found, experimentation with pharmacological activators of key
neuromodulatory systems can be done to try to rescue or enhance metaplasticity
(e.g. Gelinas and Nguyen,
2005). This would shed light on the mechanisms that regulate
metaplasticity and might reveal potentially useful strategies for enhancing
types of synaptic plasticity that may control neural information
processing.
|
Inbred mouse strains do not offer the empirical precision that is the
hallmark of directed mutagenesis (i.e. transgenic and genetic deletion
technologies). Reverse genetics is still the paradigm par excellence
for elucidating the roles of specific molecules in brain physiology and
cognition. Nonetheless, studies of the physiology and behaviours of inbred
mice can facilitate the unbiased discovery of biological and genetic
correlations that may help identify the genes and molecular mechanisms that
cause specific phenotypes. That inbred strains show diverse behavioural and
synaptic phenotypes suggests that natural variation, and variation under
laboratory conditions, exist at the genetic level. This genetic variance
allows for the elucidation of the genetic bases of these phenotypes
(Wehner et al., 2001;
Schimanski and Nguyen, 2004).
More importantly, it allows for a less biased test of the relationship between
LTP and memory.
There are some disadvantages to studying inbred strains. Because genetic
differences between strains are not imposed by the experimenter, it can be
difficult to discern exactly which genes are different between strains. Also,
because many phenotypes are polygenic, it is a challenge to determine which
genes are responsible for these phenotypes. These difficulties can be
partially resolved by incorporating sophisticated, and sometimes complex,
genetic analyses (e.g. quantitative trait loci, or QTL, analysis; microarray
techniques) (for reviews, see Wehner et
al., 2001; Schimanski and
Nguyen, 2004).
Phenotypic analysis of inbred strains should use multidisciplinary
approaches. For example, biochemical techniques may be used to quantify the
activities of key protein kinases and protein phosphatases in hippocampal
tissue derived from inbred strains. These enzymes are important for mediating
synaptic plasticity and memory function
(Micheau and Riedel, 1999;
Nguyen and Woo, 2003).
Proteomic approaches that include mass spectrometric methods aimed at
identifying phosphorylated proteins should be used to identify the substrates
of protein kinases that may be altered in memory-impaired inbred strains
(Oda et al., 2001;
Mann et al., 2002). Gene
expression analysis may identify transcripts that are altered in particular
inbred strains and that may cause behavioural or synaptic phenotypes.
Variations in the structure of specific brain regions need to be compared
among strains, as they may have an important influence on behaviour (e.g.
Crusio et al., 1987).
Functional magnetic resonance imaging
(Small et al., 2000) (see also
Weissleder et al., 2000) may
be employed to identify brain regions with structural or functional
modifications that may be associated with altered cognitive performance in
some inbred mouse strains. An example of the utility of inbred mice for
linking specific brain structures to particular memory functions is the study
by Schimanski et al. (Schimanski et al.,
2002). Inbred mice lacking intact hippocampal commissures
displayed robust long-term memory for contextual fear, but showed impaired
extinction of contextual fear memory; both processes rely on hippocampal
information processing. Defective memory extinction was correlated with
deficits in hippocampal short-term synaptic facilitation. Thus, the use of
multidisciplinary approaches can reveal novel links between brain and
behaviour.
Identification of mouse models of memory function is needed to establish
the causes of impaired memory. Presently, some inbred strains that possess
specific memory impairments have been identified (reviewed by
Schimanski and Nguyen, 2004)
(see also Table 1). These
strains should be phenotyped further, by using multiple tests of hippocampal
learning and memory (e.g. radial arm maze, object recognition, social
transmission of food preference). These tests are needed to confirm that
memory deficits are products of hippocampal dysfunction per se.
Murine `physiome' databases may be generated, and then used with murine
genomic data, to identify the genetic and molecular bases of synaptic
alterations and mnemonic deficits. Specific mechanistic hypotheses, based on
data obtained from studies performed on mutant mice and on other animal
species, can then be formulated to drive and refine experimentation. Thus,
phenotyping of inbred mice should add to, and consolidate, the knowledge
gained from studies of mutant mice. There is also the promising prospect of
testing treatments for memory deficits in many of these inbred strains. This
might involve rescuing memory by genetic or pharmacological treatments that
target specific proteins that have been identified by phenotypic and proteomic
analyses as likely causes of memory dysfunction.
Abbreviations
-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate
Acknowledgments
My research has been funded by the Alberta Heritage Foundation for Medical Research, the Alberta Paraplegic Foundation, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. I am grateful to the following colleagues for their contributions to much of the research reviewed here: Ted Abel, Steven Duffy, Jennifer Gelinas, Lesley Schimanski, Newton Woo and Jennie Young. I apologize to colleagues whose research was not discussed because of space limitations.
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