1Department of Neurology, 2Department of Neuroscience, and 3Department of Pediatrics, Albert Einstein College of Medicine; and 4Center for Epilepsy Management, Montefiore Medical Center, Bronx 10461; 5Mercy College, Dobbs Ferry, New York 10522; and 6Novartis Pharmaceuticals, East Hanover, New Jersey 06851
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ABSTRACT |
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Hedberg, Thomas G.,
Ellen F. Sperber,
Jana Velíková, and
Solomon L. Moshé.
Laminar and Temporal Heterogeneity of NMDA/Metabotropic Glutamate
Receptor Binding in Posterior Cingulate Cortex.
J. Neurophysiol. 84: 1881-1887, 2000.
Both
N-methyl-D-aspartate (NMDA) and
quisqualate/AMPA-insensitive metabotropic glutamate (mGlu) receptors
mediate plasticity induction in neocortex, but their interlaminar
distribution in cortical microcircuits is largely unknown. We used
(+)3H-MK801 and
3H-glutamate binding plus saturating
concentrations of NMDA, AMPA, and quisqualate to autoradiographically
map NMDA and mGlu receptor sites by lamina in posterior cingulate
cortex in adult male rats. Specific binding at NMDA receptor sites in
laminae II/III and VI was significantly reduced in comparison to other
laminae. Brains prepared from rats killed during dark phase of a
12h/12h light/dark cycle showed a mean 129% increase in overall
(+)3H-MK801 binding versus light phase brains but
retained reduced binding densities in laminae II/III and VI. In
contrast to NMDA findings, specific binding at mGlu sites was
consistently elevated during light phase in both laminae II/III and VI.
Specific 3H-glutamate binding in dark-phase
brains showed an overall 147% increase versus light phase binding but
did not retain significant interlaminar heterogeneity. Interpreted in
accordance with our physiologically derived models of
hippocampo-cortical microcircuitry, these results suggest that spatial
and temporal variations in glutamate receptor distribution may play an
important role in intracingulate neural processing of afferent input
from hippocampus.
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INTRODUCTION |
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Posterior cingulate cortex (PCC)
or cortical area 29 (Brodmann 1909) is involved in
associative learning and memory (Gabriel et al. 1987
),
affect (White and Sweet 1969
), and pain mechanisms (Khachaturian et al. 1983
). Prominent afferents to PCC
include excitatory projections from subiculum to lamina II/III via the subiculo-cingulate tract (SCT), a nonreciprocal afferent projection, and from anterior thalamic nuclei to laminae I and V (Peters and Jones 1985
). Numerous synaptic mechanisms in PCC underlie the processing of inputs driven by SCT excitation. Intracellular and single-unit recordings show that single-pulse subicular stimulation elicits markedly asynchronous responses in superficial (II/III-IV) and
deep (V-VI) laminae pyramidal neurons (Hedberg and Stanton 1995
). Although SCT terminates almost exclusively in
superficial lamina II/III, pyramidal cells with somata and basal
dendritic arborizations in this region do not respond monosynaptically
to subicular stimulation but show polysynaptic mixed
excitatory/inhibitory postsynaptic potentials. In contrast, deep
laminae neurons with superficially ramifying apical dendritic arbors
show mono- and disynaptic excitatory drive (Finch et al.
1984
; Hedberg et al. 1993
). These findings
suggest that PCC may process excitatory input from SCT via a synaptic
loop. Monosynaptic excitation of deep lamina pyramidal neurons by their
apical dendritic arbors allows transmission, via ascending axonal
collaterals, of largely unmodified hippocampal input to neural plexi in
superficial laminae for processing and re-excitation. In vivo as well
as in vitro tests of predicted PCC microcircuit response properties
have supported these interpretations (Finch et al. 1984
;
Hedberg and Stanton 1995
; Hedberg et al.
1993
).
In addition to acute modulation of input signal processing, excitatory
amino acid neurotransmitters are responsible for induction, expression
and maintenance of synaptic plasticity.
N-methyl-D-aspartate (NMDA)-type ionotropic
receptors mediate most long-term potentiation (LTP) in mammalian CNS
(Harris et al. 1984; Monaghan et al.
1989
). Metabotropic glutamate receptors have been implicated in
the induction of LTP as well as long-term depression (LTD) (Kato
1993
; Zheng and Gallagher 1992
). Experiments
using the mGlu blocker DL-AP3, and the NMDA blocker
D-AP5 indicate that while monosynaptic responses to SCT
stimulation require both mGlu and NMDA receptors for plasticity induction, a potentially distinct population of di- or trisynaptically activated deep lamina pyramidal neurons (not driven directly by SCT
input), may require only NMDA receptors. These synapses do not lose
their plasticity when mGlu sites are blocked (Hedberg and
Stanton 1996
). Despite intriguing suggestions provided by these
electrophysiologic findings, the interlaminar distribution and
expression of these receptors has not yet been determined in PCC.
Receptor expression can show marked circadian variability
(Holmes et al. 1997; Masson-Pevet et al.
1996
), and glutamate receptors should be mapped temporally, as
well as spatially, onto microcircuit models of PCC. Early work by
Kafka et al. (1983
, 1986
) has demonstrated that receptor
Bmax can display a strong diurnal
oscillation in the plasma membrane. In PCC, muscimol and baclofen
binding sampled at two midpoints of a light/dark cycle showed that GABA
receptors followed a daily shift in binding affinity (Hedberg
and Vogt 1988
). Glutamate receptors in this region may show
similar patterns of circadian variability.
Assembling our earlier work on the involvement of PCC in signal processing and gating, the role of glutamate receptors in plasticity induction, and the influences potentially exerted on both functions by diurnal oscillations in receptor availability, the fine spatial and temporal mapping of glutamate receptors in PCC is a critical step toward refinement and verification of models of hippocamal-cortical interaction. The present work addresses four outstanding issues: 1) since neural processing in PCC is highly stratified by lamina, we expect receptor distribution to be correspondingly heterogeneous and segregated both by origin and terminal field of major projections; 2) distribution and density of NMDA versus mGlu receptors should correspond with circuitries mediating induction of long- and short-term plasticity induction in PCC; 3) we expect light-phase/dark-phase differences in binding to reflect diurnal oscillations in receptor expression/affinity and affects on information processing; 4) glutamate receptor distribution should complement processing, potentiation, and gating functions in PCC and shed light on mechanisms governing conductance/generalization of epileptic seizures having a complete or partial origin in hippocampus.
In the present study we used quantitative tritium autoradiography (grain counts) to provide an accurate and quantifiable picture of receptor distribution and density across neocortical laminae in adult rats kept on a light/dark diurnal cycle. The fine spatial resolution achieved with this technique is necessary for interlaminar discrimination of receptor binding and responsiveness to potentially small circadian variabilities in binding pattern and density.
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METHODS |
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Tissue preparation
Adult male Sprague-Dawley rats (150-250 g) were maintained for
10-14 days prior to death on a 12h light/12h dark cycle. To prepare
tissue for binding, half the animals were decapitated in the middle of
their subjective day (photoperiod). The remaining animals were killed
at the midpoint of their subjective night (scotoperiod). Brains were
removed, and segments containing PCC were frozen in methylbutane at
35°C and stored at
70°C.
Binding assays
Frozen blocks were cut at 20°C. Coronal sections containing
most of the rostrocaudal extent of PCC were cut 20 µm thick on a
cryostat and then thaw-mounted on chrom-alum subbed glass slides, three
sections to a slide. Mounted sections were used for binding after
warming to room temperature. To initiate binding assays, all slides
were first preincubated in 50 mM Tris-HCL (pH 7.4), 2.5 mM CaCl2, and
30 mM KSCN (or 100 mM thiocyanate), for 40 min at 4°C to enable
dissociation of bound, endogenous ligand (Hedberg and Vogt
1988
). Sections were then dried with a stream of warm air.
NMDA ASSAY. NMDA sections were transferred to fresh dishes and incubated for 15 min in the same buffer with an NMDA antagonist: 20 nM (+)3H-MK801 (NEN [NET-972]; specific activity 250 µCi). To evaluate nonspecific binding, half the preincubated sections were coincubated with a solution of 100 µM unlabeled ligand and 20 nM tritiated ligand for 15 min. Binding was terminated when sections were washed in fresh buffer for 2 min at 4°C (3 times), washed again in cold distilled water for 2 min at 4°C (1 time) and then dried with a jet of cool air.
MGLU ASSAY.
To achieve saturable binding of both the high-affinity (mGluR type 1)
and low-affinity (mGluR type 2) binding sites, mGluR sections were
transferred to the same buffer in fresh dishes. Sections were then
incubated for 45 min with 250 nM 3H-glutamate
(Amersham; specific activity 45-56 Ci/mmol) in the presence of
saturating concentrations of NMDA (100 µM), AMPA (10 µM), and
quisqualate (2.5 µM; blockage of the high-affinity site only)
(Catania et al. 1994; Cha et al. 1990
).
Effective displacers of mGluR binding are quisqualate,
L-glutamate, ibotenate and trans-ACPD. Kainate
receptors were not selectively blocked in this work since their
representation in 29c is minimal (Miller et al. 1990
).
Further, since pilot work showed no quantitative difference between
3H-glutamate-incubated slides where the
high-affinity site had been blocked and those in which both sites were
accessible to binding, both sets were used in data analysis.
Nonspecific binding for both groups was evaluated by coincubating half
the sections with 1 mM glutamate for 15-20 min. Binding was terminated
by washing sections in fresh buffer for 2 min at 4°C (3 times) and
then once in cold distilled water for 2 min at 4°C. All slides were
then given two 2-min washes with 2.5% glutaraldehyde in acetone and dried with a jet of cool air.
Autoradiography
Glass coverslips (No. 00 Corning Glass) were dipped in Kodak
NTB-2 emulsion and allowed to drip dry in a darkroom. Later each emulsion-coated coverslip was tightly apposed to the bound,
slide-mounted sections by gluing one end to the frosted portion of the
slide with cyanoacrylate. Next, coverslips were sandwiched between the section-bearing slide and another clean glass slide with both held in
place by a metal binder clip. Up to 150 days were allowed for exposure,
during which time slide/coverslip packages were maintained at 70°C
in a dark container. Appropriate exposure time was determined by
examining trial sections starting 90 days after the coverslip was
affixed. At the end of the exposure period, the binder clips were
removed, and the coverslip was eased away from one end of the slide
with a toothpick. Coverslips were developed using Kodak D-19 developer
and fixed with Kodak rapid fix without hardener. Immediately after
developing, underlying sections were stained with cresyl violet.
Coverslips were then re-apposed to their slides, and a mounting medium
was used to seal the slide-coverslip package. This arrangement allowed
exposed grains lying directly over tritium-bound neuronal elements to
be studied using both lightfield and darkfield techniques.
Autoradiogram quantification
Cresyl-violet staining permitted identification of cortical area and laminae on the basis of cell type and density. In PCC, grain count/lamina was determined using a three-step procedure. First, the region of study was identified in each section at ×25, scanned into a Macintosh Quadra 840av computer, and then printed as a brightfield image. Second, starting at the midline pia mater of each coronal section, and moving laterally toward lamina VI, a series of brightfield images at ×400 encompassing a 80 × 60 µm field-of-view region (count window) were generated in laminae Ia-c through VI using contiguous window placements. Third, each count window was switched to darkfield and the focus adjusted to reveal positive (bright) images of individual silver grains. Grains within each 480-µm2 window were then counted using isolation contrast enhancement grain-counting software (IPLab, Signal Analytics). In laminae Ia-c, II/III, and IV, the count window encompassed virtually all of each region's lateral extent. In lamina Va-b, the three contiguous count windows covered the region's lateral extent. Lamina VI was located by visual inspection of the more distal aspects of the section, and a seventh and final count was taken from a centrally placed window.
Miscounts due to artifact and overlapping grains were both visually
corrected and filtered out of the count by presetting the grain size
window. Uniformity of emulsion was determined for each section by
subtracting mean grain counts made on four regions of the coverslip,
two above and two below each tissue section under study. Specific
binding was determined by further subtracting nonspecific from total
binding for each area of interest. Mean specific binding was calculated
for each region studied, and a mean ± SE was calculated for each
group of animals. Interlaminar variations in binding were assessed by
normalizing each section to a 100% baseline and then comparing laminar
binding on the basis of percent change (%) from baseline for mean
values compiled for each lamina. Further analysis involved a second
internal normalization in which z-score values (Hay
1963
) were computed on the basis of consistent variation from a
hypothetical trans-laminar null value. Interlaminar
heterogeneity was assessed for significance using Student's
t-test. Slide-coverslip packages were photographed using
both transillumination (brightfield) and side-illumination (darkfield).
Kd and
Bmax values were plotted by Scatchard analysis.
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RESULTS |
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NMDA receptor binding
Coronal sections from 10 animals were used: 7 taken at mid-photoperiod, and 3 taken at mid-scotoperiod. Each brain provided ~40 sections. In sections exposed to (+)3H-MK801 (plus cold-chase ligand for specific binding), patterns of grain density reflecting receptor distribution were evident under darkfield visual inspection. Binding at NMDA sites was dense both in anterior (bregma: 2.5-5.4) and posterior (bregma: 5.5-7.7) sections of PCC. In contrast, control binding was low (<10% of specific) in all sections. There was no evidence of significant interlaminar variations in control binding in anterior or posterior sections taken from animals killed during the midpoints of either photoperiod or scotoperiod.
Specific binding was consistently pronounced in molecular sublaminae Ia through Ic (a largely acellular region of dendritic arborization), where quantification of each scanned section gave a mean of ~4,000 grains/480 µm2. Since per-lamina grain counts were a function of overall binding density (which did vary between slides with emulsion thickness and radioisotope penetrance variables), data for each section were normalized to specific binding in lamina Ia-c. Mean specific binding per lamina could thus be calculated as a percent change from the lamina Ia-c reference baseline for each section. Visual examination of interlaminar grain distribution and density in 6-12 separate sections indicated a uniform diminution in laminae II/III and VI binding density across the rostrocaudal extent of PCC (Figs. 1 and 2). Per-lamina assessments of specific binding for each condition confirmed these observations.
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As shown in Fig. 2A, normalization of binding data revealed
a notable decrease, versus lamina Ia-c reference baseline, in binding
density in lamina II/III (%
=
10.2 ± 0.6%; mean ± SE; P < 0.02) in
sections taken from photoperiod animals. Likewise, binding in lamina VI
showed a concomitant drop versus baseline of
%
=
17.7 ± 3.5% (P < 0.05). A secondary internal normalization within each section was
performed to obtain a z score for mean binding in each
lamina. Again, significant comparative decrements in binding in laminae
II/III and VI indicated that (+)3H-MK-801 binding
was consistently limited in both laminae. In other laminae, grain
density varied both higher and lower than the Ia-c baseline and
revealed no consistent increases or decrements in laminar-specific binding.
At mid-scotoperiod, an overall increase in specific
(+)3H-MK801 binding was seen, with binding
density ~5,000 grains/480 µm2 tissue area.
Mean mid-scotoperiod binding averaged 128% of mean mid-photoperiod
binding, indicating that a substantial change in receptor binding
affinity or receptor availability may occur across a circadian time
frame. As seen in Fig. 2B, normalized binding densities
recorded in mid-scotoperiod sections retained the same interlaminar
proportions seen in mid-photoperiod sections and continued to show a
pronounced and significant drop in laminae II/III
(%
=
10.1 ± 2.3%; P < 0.02) and VI (
%
=
4.8 ± 1.3%; P < 0.05; Fig. 2B).
mGlu receptor binding
In contrast to binding density patterns observed using (+)3H-MK801, specific binding of 3H-glutamate was markedly reduced overall. In both photoperiod and scotoperiod brains, specific 3H-glutamate binding was three to six times less than the density of specific (+)3H-MK801 binding although all conditions showed approximately the same degree of nonspecific binding. Visual assessment of 3H-glutamate-bound sections showed grain distribution to be rather diffuse. Notwithstanding, quantitative analysis revealed a consistent pattern of specific binding different from that seen in NMDA sections.
Using specific binding in lamina Ia-c as baseline, sections obtained
in mid-photoperiod showed consistent increases in
3H-glutamate binding density in laminae II/III
through VI (Fig. 3A).
Normalized data, with the exception of sublamina Vb
(%
= +3.9 ± 8.8%; P > 0.05), showed pronounced binding density increases in laminae II/III
(
%
= +11.4 ± 4.9%; P < 0.02) through VI (
%
= +15.3 ± 8.5%; P < 0.05). These patterns of binding density
appear to be an inversion, or mirror image of binding patterns seen in laminae II/III and VI in (+)3H-MK801-exposed
sections. As shown in Fig. 4, binding at mGlu receptor sites was
again substantially elevated in animals killed at mid-scotoperiod. The
overall increase in mGlu binding density of +147% across all laminae
paralleled a similar elevation (+128%) in
(+)3H-MK801-bound sections. On the other hand,
the interlaminar heterogeneities seen in mid-photoperiod animals were
absent (P > 0.05 for both lamina II/III and VI).
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DISCUSSION |
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This study has shown that NMDA-specific binding sites are
distributed heterogeneously, both spatially and temporally, throughout PCC. They are comparatively reduced in lamina II/III, the primary terminal field for excitatory inflow from subiculum, and in lamina VI,
the origin of most extracingulate efferents (Peters and Jones 1985). We have also shown that while mGlu binding is
comparatively sparse throughout PCC, it has an inverted or mirror-image
complementarity with NMDA binding in laminae II/III through VI.
Finally, specific binding at both NMDA and mGlu receptor sites
underwent a marked 24-h variation in response to diurnal changes in
either receptor expression or affinity (Fig.
4).
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Grain-density patterns quantified in this study appear to represent physiologic heterogeneities in the binding of glutamate radioligands to specific receptor sites for the following reasons: nonspecific binding was consistently low and largely invariant among animals, sections, and slides for both NMDA and mGluR sites; laminar-specific heterogeneities in binding density were similar from section to section across all animals; and mGlu binding showed increases at the same locations where NMDA binding showed decreases. Together these factors imply a physiologic etiology rather than tissue damage or artifact and suggest that radioligand binding occurred at specific receptor sites.
Interlaminar heterogeneities in binding density may reflect circadian
oscillations in both pre- and postsynaptic receptors that impose cyclic
short-term changes in the functional integrity of PCC microcircuitries.
Diurnal oscillations in neurotransmitter expression, genetic
composition, binding affinity, and mechanism of action have been
reported in hippocampus and elsewhere for GABAA
(Kanterewicz et al. 1995); 5-HT2c (Holmes et al.
1997
), melatonin (Masson-Pevet et al. 1996
), and
NMDA (Ding et al. 1998
) receptors. Oscillations in
receptor binding and action have been linked with mood and affective
states (Borsook et al. 1984
) and are critical to the
linking of photic and other time cues with endogenous neurohormonal
oscillations (Wirz-Justice 1987
). The nocturnal
up-regulation of receptor availability/affinity seen in this study
during the animal's subjective night, yielded an oscillating ratio of
NMDA (primarily LTP) to mGlu (primarily LTD) receptor binding. This,
along with concomitant loss of the interlaminar 3H-glutamate binding heterogeneity characteristic
of photoperiod binding, could significantly influence the expression of
long-term plasticity in PCC information-processing networks. Further,
we sampled only the putative peak and trough of a likely sinusoidal oscillation in receptor binding. Additional temporal features of these
changes may thus not be reflected here.
The anatomic findings discussed in the preceding text may acquire
greater significance in light of earlier in vitro (Hedberg et
al. 1993) and in vivo (Hedberg and Stanton 1996
)
electrophysiologic work. In both studies cited, the response of PCC to
subicular stimulation was stereotypic and highly influenced by the
frequency/amplitude of synaptic inflow via SCT. When stimulation
frequency exceeded 8 Hz (or dropped < 4 Hz), processing subroutines
were elicited in superficial laminae, and the discharge rate of
polysynaptically driven deep laminar (V-VI) pyramidal cells became
asynchronous. However, when stimulation frequency moved into the 4- to
8-Hz window (approximating the theta spikes seen in EEG records), both superficial and deep laminar neuronal discharge became coincident. As
shown in Fig. 5, this direct relay of a
narrowband of amplitude and frequency-modulated signals enabled mono-
and polysynaptically driven pyramidal output to extracingulate targets
to become essentially synchronous, of enhanced amplitude, and liable to
LTP induction.
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The existence of a mechanism which enables plasticity induction in
deep-laminar pyramids is supported by the sharp reduction in NMDA
receptor representation in the principal terminal field of SCT (lamina
II/III). Since NMDA-type glutamate receptors are the primary
transducers of LTP induction in neocortex (Dudek and Bear
1992), it is reasonable to posit that their representation should be reduced where the microcircuitry of PCC is first
activated. Otherwise plasticity at this primary synaptic junction could
alter input to PCC and compromise its information-processing function. The relative increase in co-localized mGlu receptor sites becomes important in this context. Since mGlu receptors are known to mediate LTD (Kato 1993
), a nullifying balance between the two
receptors, augmented by the inhibitory influence of local-circuit
interneurons, could account for nonplastic monosynaptic activation of
PCC by frequency/amplitude coded hippocampal input.
This same model may explain the dense binding at NMDA sites in laminae
I and Vb. If monosynaptic excitation by SCT of lamina V pyramidal
neurons is nonplastic at apical dendritic synapses (Hedberg and
Stanton 1996), polysynaptic activation must be responsible for
long-term changes. Thus as modeled in Fig.
6, SCT-driven LTP/LTD could arise in deep
lamina pyramidal neurons if: the synaptic input required to induce
plasticity was not disrupted by upper laminar PCC processing (e.g.,
during theta-frequency tetanic stimulation or "theta-gating") and
plasticity-inducing SCT input was relayed to deep laminae pyramidal
neurons by NMDA receptors at dendritic/somatal synapses formed by axon
collaterals of monosynaptically driven lamina Vb neurons. In support of
this, the field potential representing SCT-elicited discharge of
deep-lamina PCC pyramidal neurons is best potentiated by theta-pulse
tetanic stimulation (Stanton et al. 1994
); inhibited
from LTP by the NMDA-specific antagonist D-AP5; and
unaffected by the mGlu-specific antagonist DL-AP3
(Hedberg and Stanton 1996
). Large pyramidal neurons in
lamina VI comprise the final extracingulate output for PCC-processed
information (Donovan and Wyss 1983
; Meibach and
Seigel 1977
). Synaptic inflow converging on their basal
dendrites arises largely from extracingulate sources (e.g., anterior
thalamic nuclei) while intracingulate projections terminate at their
highly branched and extremely spiny dendritic tuft arborizations in
lamina Ia-c. Responses to PCC processing would occur primarily at
subpial apical tufts, while basal dendritic (extracingulate) inputs
should be plasticity-free.
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Disruption of the integrity of this system may contribute to the
etiology of certain convulsive disorders. An interesting question bears
on how (given the glutamate receptor distribution mapped in this study)
models of plasticity induction and theta-gating in PCC can account for
the amplification or inhibition of propagated rhythmic/epileptiform
neural activity. In healthy (nonepileptic) brains, gating of
hippocampal output may be damped or modulated so that otherwise
preictal theta yields relatively normal EEGs. In seizure-prone brains,
theta-gating may be abnormal (thalamic quiescence and/or facilitation
of unmodified 1:1 SCT throughput), and damping may be lost, a
potentially catastrophic circumstance given PCC's multiple projections
to thalamus, motor cortex, pons, periaqueductal gray, etc.
(Swanson and Cowan 1977).
The synchronous and rhythmic discharge of large populations of
neurons during an epileptic seizure may be akin to our 4- to 8-Hz
stimulation protocol. While theta frequency input itself cannot give rise to synaptic plasticity, Stanton et
al. (1994) have shown that "theta-burst" stimulation most
effectively induces hippocampal LTP. Theta-burst stimulation uses a
frequency-modulated 4- to 8-Hz signal containing an amplitude-modulated
component (the discharge frequency of neurons represented within each
successive wave of afferent excitation). With a failure of superficial
modulatory mechanisms, not only can theta frequencies open up a 1:1
throughput conduit for epileptic output from hippocampus, but the
presence of 80- to 120-Hz excitatory activity within each theta wave
can potentiate that pathway, making it more susceptible to future epileptic activity. Potentiated, theta-gated activity, strengthened and
facilitated by its passage through PCC, may contribute significantly to
seizure generalization.
These findings may have intriguing long-range applications. If theta-gating dysfunction has a pharmacologic base (such as NMDA, mGlu or AMPA hypo/hyperexpression), drug-based treatments are indicated. Given a laminar-specific circadian oscillation in binding patterns, maximal efficacy of any such pharmacotherapy might be achieved by appropriate timing of drug administration. Seizure activity is often linked to a specific time of day, and such oscillations in facilitatory pathways may play a role in these temporal characteristics. Should the etiology encompass dysfunction in the microcircuit processing of AM/FM characteristics of thalamic/hippocampal inputs, an electrophysiologic route is plausible; e.g., an implantable, frequency-sensitive neuroprosthesis could be tuned to respond to preictal signals by emitting a burst of de-synchronizing stimuli in critical neocortical regions. Additional clarification of the cellular distribution of plasticity-sensitive glutamate receptors within the PCC microcircuit will permit a much more profound understanding of the way this critical hippocampal-cortical interface functions.
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ACKNOWLEDGMENTS |
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S. L. Moshé is a recipient of the Martin A. and Emily L. Fisher Fellowship in Neurology and Pediatrics.
This work was partially supported by National Institute of Neurological
Disorders and Stroke Grants NS-20253 (S. L. Moshé), NS-36238
(J. Velíková), and NS-30387 (E. F. Sperber).
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FOOTNOTES |
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Address for reprint requests: T. G. Hedberg, Depts. Neurology and Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461 (E-mail: thomas.hedberg{at}pharma.novartis.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 24 November 1999; accepted in final form 8 June 2000.
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REFERENCES |
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