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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. A bipolar stimulating electrode
was placed on the Schaffer collateral and commissural (comm.) fibers. Recording
electrodes placed in the dendritic layer and/or the pyramidal layer of CA1 will
record an Excitatory Postsynaptic Potential (EPSP) or a population spike (PS)
following stimulation, respectively. As discussed in the text the EPSP
represents the response at the CA3-CA1 synapse and the PS represents the number
of pyramidal cells firing and the contribution of the EPSP at that location. The
top portion of the figure demonstrates the four layers that the CA1 pyramidal
neuron lies within (S. denotes Stratum). The small neuron with a letter “I”
represents an inhibitory interneuron. The pathway diagramed in the top portion
of the figure corresponds to the recurrent inhibitory loop in area CA1.
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 CA3ÞCA1 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 SC’s. 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 EPSP’s 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.
The major inhibitory neurotransmitter in the hippocampus is GABA (Roberts 1976).
Eliciting a single evoked potential via stimulation of the SC’s 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 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
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
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 SC’s 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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