Abstract : Cortical spreading
depression (CSD) is believed to be a putative
neuronal mechanism underlying migraine aura and
subsequent pain. In vitro and ex vivo/in vitro
brain slice techniques were used to investigate
CSD effects on the field excitatory postsynaptic
potentials (fEPSP) and tetanus-induced long-term
potentiation (LTP) in combined rat
hippocampus-cortex slices. Induction of CSD in
combined hippocampus-cortex slices in which DC
negative deflections did not propagate from
neocortex to hippocampus significantly augmented
fEPSP amplitude and LTP in the hippocampus.
Propagation of CSD to the hippocampus
resulted in a transient suppression followed by
reinstatement of fEPSP with amplitude of pre-CSD
levels. LTP was inhibited when DC potential
shifts were recorded in the hippocampus.
Furthermore, CSD was induced in anaesthetized
rats and, thereafter, hippocampal tissues were
examined in vitro. LTP was significantly
enhanced in hippocampal slices obtained from
ipsilateral site to the hemisphere in which CSD
was evoked.
The results indicate the disturbances of
hippocampal synaptic transmission triggered by
propagation of CSD. This perturbation of
hippocampal synaptic transmission induced by CSD
may relate to some symptoms occurring during
migraine attacks, such as amnesia and
hyperactivity.
Introduction
Spreading depression (SD) is a pronounced
self-propagating depolarization of neurons and
glia with a transient massive redistribution of
ions between intracellular and extracellular
compartments.
SD spreads slowly from the site of onset as
a radial wave across the neuronal tissues
followed by a transient period of depressed
bioelectrical activity (Leao, 1944; Somjen,
2001).
Studies on the human brain suggested that SD
might be a clinical phenomenon. SD occurred
following head injury or intracranial
haemorrhage in human neocortex (Mayevsky et al.,
1996; Strong et al., 2002), and SD-like waves
were observed during the aura phase of migraine
attacks (Hadjikhani et al., 2001).
Furthermore, experimental investigations
indicated that SD may also play a role in
transient global amnesia, epilepsy (Gorji, 2001;
Gorji & Speckmann, 2004) and spinal cord
disorders (Vinogradova et al., 1991; Gorji et
al., 2004). SD was originally linked to the aura
phase of migraine (Lashley, 1941; Leao &
Morrison, 1945; Pearce, 1985).
However, some evidence suggested that SD is
also implicated in migraine pain as well as
other signs and symptoms such as amnesia,
hyperactivity, drowsiness and
yawning,
sexual arousal, nausea and vomiting, pupil
reaction, and fluid retention (Gorji,
2001).
The potential interrelation of SD and
migraine has usually involved neocortical
tissues, and the possible roles in other brain
regions including the hippocampus were not fully
investigated. The hippocampus has direct and
important functional interactions with brain
areas likely to be important to migraine, such
as the areas associated with vision, emotions
and neuroendocrine homeostasis.
The connection between entorhinal cortex and
hippocampus is regarded as an important loop
responsible for the processing of sensory
information (Vaisanen et al., 1999). Thus, these
medial temporal lobe structures may play a
crucial role in the development of somatosensory
and neuropsychotic symptoms in neurological
disorders such as epilepsy and migraine (Eid et
al., 1995).
As memories in humans depend initially on
the medial temporal lobe system, including the
hippocampus, it was suggested that interictal
memory dysfunction in patients with migraine
might be attributed to the hippocampus
involvement (Kupfermann, 1966; Kapp &
Schneider, 1971). Furthermore, propagation of SD
in the hippocampus was believed to play a role
in migraine pain by triggering nociceptive
activation of the caudal trigeminal nucleus
(Kunkler & Kraig, 2003).
Classical studies investigated hippocampal
SD more often by implantation of KCl into the
hippocampus and induction of SD directly in the
tissue. Little information is available on the
effects of cortical spreading depression (CSD)
on hippocampal activity. Because altered neural
circuit function can be seen remote from the SD
propagation site (Bures et al., 1961;
Albe-Fessard et al., 1984; Moskowitz et al.,
1993; Kunkler & Kraig, 2003; Gorji et al.,
2004), using in vitro and ex vivo Ú in vitro
brain models, the effects of neocortical SD on
the synaptic plasticity of hippocampal tissues
were tested.
Discussion
The present study shows how differently CSD
could affect hippocampal activity. Regarding our
findings, abortive CSD, i.e. SD that travelled
the whole neocortex and entorhinal cortex but
stopped entering the hippocampus, enhanced the
fEPSP as well as LTP in CA1 area of combined
hippocampal&endash;entorhinal cortex slices.
`
On the contrary, CSD spreading from the
temporal neocortex all the way to CA3 area
transiently suppressed evoked fEPSP and reduced
LTP in the hippocampal tissues. Intrinsic
optical imaging also revealed different patterns
of SD propagation in hippocampal and entorhinal
slices (Buchheim et al., 2002). Although the
exact mechanisms responsible for different
propagation patterns of SD are not clear, some
hypotheses can be derived from experimental
data. A traditional view assumes that the
entorhinal cortices faithfully transmit
neocortical inputs to the hippocampus and vice
versa (Naber et al., 1999).
More recent evidence suggests that the
entorhinal cortices are more than a simple relay
between the neocortex and hippocampus.
Entorhinal cortices contribute to the gating of
impulses between these structures. Local
inhibition and intrinsic membrane properties of
entorhinal neurons are major factors limiting
impulse traffic across the entorhinal cortex
(Pelletier et al., 2004).
Consistent with this, physiological studies
have disclosed the existence of powerful
inhibition in the entorhinal cortex (Finch et
al., 1986; Jones & Buhl, 1993; Funahashi
& Stewart, 1998), which may act to abort the
propagation of SD. Furthermore, some studies
indicated a relative resistance of SD occurrence
in the hippocampus compared with entorhinal
cortex (Dalby & Mody, 2003; Faria &
Mody, 2004). `
The failure of cortical SD to propagate to
the hippocampus was reported earlier (Fifkova,
1964). The release of glutamate is essential to
the propagation of cortical SD (Van Harreveld
& Fifkova, 1973). Several studies have shown
that glutamate acts via NMDA receptors during
the generation and propagation of SD (Mody et
al., 1987; Gorji, 2001). The NMDA receptor is a
heterotetramer assembled from NR1 subunits and
at least one subtype of the four members of the
NR2(A&endash;D) subunits family. NR2B subunits
are essential to the generation and propagation
of SD in entorhinal cortical slices (Faria &
Mody, 2004). The physiological characteristics
and possibly the localization of NR2B subunits
at synapses differ between the entorhinal cortex
and the hippocampus (Gordey et al., 2001; Faria
& Mody, 2004), which, in turn, may influence
SD penetration into the hippocampus.
Seventy per cent of CSD waves propagating
from temporal cortex slices penetrated to
adjacent entorhinal cortex slices and stopped
there, whereas the remaining 30% reached CA1 and
CA3 regions of the hippocampal slices. On the
other hand, CSD elicited from the somatosensory
neocortex of anaesthetized rats did not
penetrate into the hippocampus.
This suggests that the CSD recording in
slices offers better conditions for SD
propagation probably due to weakening of
intrahippocampal inhibitory mechanisms. The
entorhinal cortex, a palaeocortical area,
receives projections from secondary and higher
associative areas of the neocortex. Regions of
both ipsilateral frontal and temporal lobes are
found to contribute afferents to this region of
the brain.
The association areas from the primary
sensory modalities of vision, audition and
somesthesis project to multimodal convergence
areas in the frontal and parietal lobes (Pandya
& Kuypers, 1969). Both multimodal regions
project in turn to the cingulate gyrus on the
medial surface of the hemisphere, which
contributes a heavy supply of afferents to the
presubiculum and entorhinal cortex (Jones &
Powell, 1970). Thus, the entorhinal cortex is a
final cortical link between the sensory systems
of the neocortex and the hippocampus of the
limbic system. From the entorhinal input, the
hippocampus receives highly complex and
differentiated signals, coding information about
the properties of the applied stimuli. The
entorhinal cortical neurons constitute the
direct perforant path and the crossed
temporoammonic path to the hippocampus. They
terminate on dendritic branches of
CA1&endash;CA3 and the dentate fascia neurons
(Van Hoesen et al., 1972). In the present study,
transient sensory cortical dysfunction induced
by abortive SD enhanced hippocampal activity.
This suggests an inhibitory tone mediated
through neocortical influence on hippocampal
plasticity. Our conclusion is supported by
recent evidence indicating that elimination of
cortical input resulted in increased reactivity
and complete disappearance of habituation, with
prolongation of tonic responses in the
hippocampus (Vinogradova, 2001). Lesions of the
entorhinal cortex in adolescent rats also
resulted in augmented spontaneous locomotor
activity, an effect possibly mediated by
postsynaptic hypersensitivity (Sumiyoshi et al.,
2004). LTP is an experimental phenomenon, which
can be used to demonstrate the repertoire of
long-lasting modifications of which individual
synapses are capable.
LTP remains one of the prime candidates for
mediating learning and memory as well as many
other forms of experience-dependent plasticity
(Malenka & Bear, 2004). In the present
study, functional disruption of neocortical
input to the hippocampus induced by abortive SD
in both in vitro and ex vivo experiments
enhanced the LTP in the CA1 hippocampal area
ipsilateral to SD initiation.
Enhancement of LTP by abortive SD was NMDA
receptor dependent, as APV blocked LTP
induction. Further propagation of SD to the
hippocampus, conversely, inhibits LTP. These
data indicate the modulatory role of SD on the
efficacy of the hippocampal synaptic
transmission. In line with our results, CSD
visualized using manganese-enhanced MRI
following topical application of KCl to the
exposed rat cortex revealed signal enhancement
in CA1&endash;3 areas, the subiculum and the
dentate gyrus of the hippocampus (Henning et
al., 2005).
The increase in synaptic responsiveness
associated with LTP has been discussed to be
detrimental to neuronal function in the sense
that it can promote seizure activity (Johnston,
1996). It is thus interesting to hypothesize
that the facilitatory effect of abortive SD on
evoked synaptic activity and LTP observed in the
hippocampus may contribute to seizure generation
or epileptogenesis. Indeed, the expression of
neuronal hyperexcitability associated with SD
has been suggested to link migraine and epilepsy
(Leniger et al., 2003).
In line with this are preliminary data
indicating that SD precede epileptic activity in
human brain tissue (Gorji & Speckmann,
2005). Some evidence implicates the hippocampus
in spatial memory and navigation, learning and
emotion (Jensen & Lisman, 2005). This
structure is also related primarily to the
control of gross movements, such as locomotion
and changes in posture, and involved in certain
aspects of the pituitary&endash;adrenocortical
system. Amnesia, emotional disturbances,
hyperactivity, yawning and fluid retention were
observed in hippocampal dysfunction as well as
during migraine attacks (Bures et al., 1974;
Isaacson & Pribram, 1975; Dalessio, 1980;
Daquin et al., 2001). SD in animal experiments
also elicits similar symptoms (Gorji, 2001).
SD-like changes occur with visual aura in
patients with migraine (Hadjikhani et al.,
2001). Propagation of depolarizing waves in
sensory systems of the neocortex may directly
affect primary sensory modalities and induce
aura symptoms such as visual hallucinations. SD,
either indirectly via the effect on entorhinal
input to the hippocampus or directly by
propagation to the hippocampal structure, may
disturb the hippocampal function and lead to
symptoms such as amnesia or hyperactivity during
migraine attacks.
