Background
The hippocampus is one
of a group of structures forming the limbic system and is a part of the
hippocampal formation, which also includes the dentate gyrus, subiculum, and
entorhinal cortex. Different
components of the limbic system have been shown to play a critical role in all
aspects of emotions, fear, learning and memory (Geinisman et al. 2000a;
Geinisman 2000b; McMillan et al. 1987; Cardinal et al. 2002)
.
The initial insights on
the role of the hippocampus came from studies of amnesia in human patients
following removal of the hippocampus plus neighboring medial temporal structures
(Scoville and Milner 1956). Extensive
evidence implicates the hippocampus and related structures in the formation of
episodic memories in humans (Reilly 2001; Aggleton and Brown 1999) and in
consolidating information into long-term declarative memory (Mumby et al. 1999)
.
Hippocampal Inputs
and Outputs
The
hippocampus has direct connections to the entorhinal cortex (via the
subiculum) and the amygdala. Outputs from these structures can then affect many
other areas of the brain. For
example the entorhinal cortex projects to the cingulate cortex, which has
a connections to the temporal lobe cortex, orbital cortex, and olfactory bulb.
Thus, all of these areas can be influenced by hippocampal output, primarily from
CA1.
The
entorhinal cortex is a major
source of inputs to the hippocampus collecting information from the
cingulate cortex,
temporal lobe cortex,
amygdala, orbital
cortex, and olfactory bulb
(Johnston and Amaral 1998). The
hippocampus receives inputs via the precommissural branch of the fornix from the
septal nuclei. Figure 1.4
gives an overview of the major inputs and outputs of the hippocampus.
The
main input to the hippocampus (perforant pathway) arises from the entorhinal
cortex and passes through to the dentate gyrus. From the granule cells of
dentate gyrus connections are made to area CA3 of the hippocampus proper via
mossy fibers. CA3 sends connections
to CA1 pyramidal cells via the Schaeffer collateral (SC) as well as commissural
fibers (comm.) from the contralateral hippocampus.
The major neurotransmitter in these three pathways is glutamate.
The final output from the two CA fields passes through the subiculum
entering the alveus, fimbria, and fornix and then to other areas of the brain.
For the purposes of this dissertation I will focus on the synapse between
the CA3 to CA1 neuron. Figure
1.5 is a
Figure 1.4.
Schematic representation of hippocampal connections.
Information leaving the entorhinal cortex can enter any of the following layers: CA3, CA1 or the subiculum. Information entering the dentate gyrus predominantly follows the mossy fiber pathway to CA3. Information from CA3 leaves via the Schaffer collateral pathway for the CA1 region. Information from CA1 travels to the subiculum and then to the entorhinal cortex.
Figure 1.5.
Hippocampal pathways and their stimulation
Signals from the
entorhinal cortex (EC) enter the dentate gyrus (DG) via the perforant path (PP).
From the DG information travels to the CA3 pyramidal neurons via the
mossy fibers. From the CA3 neurons the signal leaves via the Schaffer
collaterals and joins with the commissural fibers (Comm.) from the contralateral
CA3 making connections with CA1 pyramidal neurons.
Signals leaving CA1 then travel to neurons within the subiculum.
diagrammatic
representation of the pathways entering the hippocampus and the pathways within
it.
The
highly organized and laminar arrangement of synaptic pathways makes the
hippocampus a convenient model for studying synaptic actions in
vivo and in
vitro (Andersen et al. 1971).
Electrophysiology
of the CA3ŢCA1 Synapses
Extracellular field recordings represent the
summed responses from a number of neurons in the vicinity of the recording
electrode. Because of the orderly
arrangement of the pyramidal neurons and their dendrites, electrical field
recordings offer valuable information about the temporal arrangement of
responses from apical dendrites to cell bodies.
Following stimulation of the SC and commissural fibers (Figure
1.5 stimulating electrode), an extracellular
recording electrode in the stratum radiatum (Figure
1.5 S. radiatum) containing synapses, would record
a small negative potential that results from the action potentials generated in
the presynaptic fibers (Fiber Volley, FV).
Following the FV a slow negative potential, corresponding to the
population excitatory postsynaptic potential (pEPSP), would be recorded (Figure 1.5 shows
a representative pEPSP, which will be referred to as an EPSP from now on).
The EPSP represents depolarization at the postsynaptic membrane,
indicating that transmission took place at the CA3-CA1 synapse.
Placing the recording electrode in the stratum pyramidale (Figure
1.5 S. pyramidale) would allow us to record a
positive deflection due to current exiting the basal dendrites near the cell
body. If the magnitude of the
depolarization is sufficient to bring the pyramidal cell to threshold, it will
fire one or more action potentials. These
action potentials will be recorded as a negative potential overlapping the
positive potential. This type of
recording is known as a population spike (PS) and is represented in Figure
1.5. While the EPSP is
affected by changes occurring at the synapse the PS is affected by combination
of 3 factors: 1) the amplitude of
the EPSP, 2) the passive properties of the CA1 pyramidal cell (from dendrites to
axon hillock), and 3) the level of inhibition produced by the GABAergic
interneurons innervating the CA1 pyramidal neurons.
Changes in the PS give a great deal of information about the number and
excitability of neurons involved in the final output from the hippocampus.
The CA1 Pyramidal
Neuron
Activation of the CA3 neuron leads to an increase in glutamate release
from the nerve terminals of the SCs. Glutamate
released in the stratum radiatum and stratum lacunosum moleculare of CA1
activates either ionotropic or metabotropic receptors.
The ionotropic glutamate receptors are classified into three types AMPA,
kainite, and NMDA receptors, named after the ligand initially used to
characterize them. AMPA and kainite
receptors mediate the fast EPSP seen following SC stimulation (Karnup and
Stelzer 1999). NMDA receptors
mediate slow-rising EPSPs and are thought to be responsible for some forms of
long-term synaptic plasticity (Tsien et al. 1996; Kullmann et al. 1996). Metabotropic glutamate receptors, which are
located at both the presynaptic and postsynaptic side act to modulate release of
neurotransmitter presynaptically (Lie et al. 2000; Baskys and Malenka 1991)
, and modify postsynaptic
responses (Xiao et al. 2001).
The major inhibitory neurotransmitter in the hippocampus is GABA (Roberts
1976). Eliciting
a single evoked potential via stimulation of the SCs results in a
characteristic sequence of excitation followed by inhibition when recorded from
the stratum pyramidale. In rats the
excitation typically precedes the inhibition by a few milliseconds.
The inhibition arises from feedforward and feedback connections via
inhibitory interneurons. The inhibition corresponds to the release of GABA, which
initiates two types of inhibitory responses, a fast inhibitory postsynaptic
potential (IPSP) mediated by GABAA receptors and a slow IPSP brought
on by GABAB receptor activation.
Hippocampal Synaptic Plasticity
The hippocampus exhibits short and long term synaptic plasticity.
For the purpose of our discussion plasticity will be defined as
a change in the efficiency of synaptic transmission following previous synaptic
activity.
Short-term Plasticity
Short-term
synaptic plasticity lasting from a few milliseconds to a few minutes can be
elicited, among other means by paired pulse stimulation.
Activation of the CA1
pyramidal cell by a single pulse will lead to an action potential sent out of
the hippocampus and to inhibitory interneurons within the hippocampus (Top
insert in Figure 1.5; Arrows leaving S. pyramidale). Activation of inhibitory neurons (Figure 1.5 Top
insert; Inhibitory interneuron labeled I in S. oriens) by the CA1 neurons
will lead to the recurrent inhibition of the subsequent response initiated in
the CA1 neuron by the second stimulus delivered shortly (10-13 ms) after the
first one. This type of pairing of
two pulses in rapid succession leads to an inhibition known as paired pulse
inhibition (PPI).
Changes in the ratio of
the amplitudes of the first and second evoked potentials (in a PPI experiment),
can occur through changes in both GABA receptor sensitivity and GABA release.
This has been demonstrated experimentally through, an enhancement of PPI
with GABA agonists (Rock and Taylor 1986) and a decrease in PPI by GABA
antagonists (Kapur et al. 1989, 1997)
.
If the stimuli are further apart (15-40 ms) the
second stimuli arrives, when the recurrent inhibitory loop has already been
inactivated. Therefore, the second
response is not inhibited but facilitated due to residual Ca2+
increase after the first stimulus. This
is called paired pulse facilitation (PPF).
Changes in the ratio of amplitudes of first and second potentials
are generally accepted as a modification in the presynaptic component of the
synapse (Commins et al. 1998; Chen et al. 1996; Gottschalk et al. 1998),
although alterations in postsynaptic AMPA receptors have also been reported
during PPF experiments (Wang and Kelly 1995-1997, 2001).
Long-term Plasticity
When a change in synaptic efficiency persists
for long periods of time (hours to days) it is known as long-term plasticity.
In 1973 Bliss and Lomo observed that high frequency stimulation (HFS) of
the perforant path in anaesthetized rabbits led to a potentiation of synaptic
responses which could last for several hours (Bliss and Lomo 1973).
Later many other pathways in the brain including the SCs in the
hippocampus were shown to express similar phenomenon following HFS (see review
by Recasens 1995). The general
consensus is that induction of LTP at CA1 synapses requires Ca2+
entry into the postsynaptic dendritic spine via the activation of the NMDA
receptor (Collingridge et al. 1983), however increased Ca2+
concentration through NMDA-independent mechanisms may also lead to LTP (Grover
1998; Kullmann et al. 1992)
. Therefore Ca2+
which is directly involved in PPF, also initiates the mechanisms which maintain
enhanced synaptic transmission for a long period of time (Impey et al. 1996;
Solderling and Derach 2000; Suzuki 1996)
.
The mechanism
responsible for LTP has been an area of intense debate.
Some of the more recent mechanisms proposed to explain LTP at hippocampal
synapses include: 1) an incorporation of new AMPA receptors into the membrane
(Pickard et al. 2001; Hayashi et al. 2000). 2) activation of previously silent
synapses (Malinow 1995 and Konerth 1996), and 3) HFS induced splitting of
dendritic spines allowing a synaptic response to be amplified (Jontes and Smith
2000).
Although some studies demonstrated a strong
correlation between a deficit in LTP and poor spatial memory (Sakimura et al.
1995; Abel et al. 1997), several reports described normal spatial orientation in
spite of impaired LTP (Meiri et al. 1998; Saarelainen et al. 2000; Jun et al.
1998; Bach et al. 1995). These
briefly mentioned conflicting results demonstrate some of the difficulties in
accepting LTP as the molecular mechanism of memory formation.
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