Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Hippocampus — Synaptic Organization

(Shepherd; Synaptic Organization of the Brain, Johnston; Hippocampus, 417-458)



Hippocampus is one of the most thoroughly studied areas of the mammalian central nervous system. (Johnston; Hippocampus, 417)

Hippocampal formation that includes the dentate gyrus, the hippocampus, the subiculum, presubiculum and parasubiculum, and the entorhinal cortex. (Johnston; Hippocampus, 417)

The dentate gyrus, hippocampus, and subiculum have a single cell layer with less cellular or acellular layers located above and below it. The other parts of the hippocampal formation have several cellular layers.

A patient known by his initials, H.M., underwent bilateral hippocampal removal for the treatment of intractable epilepsy. He was left with a permanent loss of the ability to encode new information into long-term memory. (Johnston; Hippocampus, 417)

Epilepsy and the Hippocampus

In addition to memory studies, the hippocampus is also of interest because of its high seizure susceptibility. It has the lowest seizure threshold of any brain region. Most patients with epilepsy have seizures that involve the hippocampus, and these seizures are often the most difficult to control medically. (Johnston; Hippocampus, 417)

Alzheimer’s Disease and the Hippocampus

Portions of the hippocampal formation, particularly the entorhinal cortex, are prime targets for the pathology associated with Alzheimer's disease, and the hippocampus is very vulnerable to the effects of ischemia and anoxia. (Johnston; Hippocampus, 418)

Pyramidal Neurons

The principal neurons in the dentate gyrus are the granule cells, and in the hippocampus they are the pyramidal neurons. (Johnston; Hippocampus, 420)

The pyramidal cell layer of the hippocampus has been divided into three regions designated CA1, CA2, CA3 based on the size and appearance of the neurons. (Johnston; Hippocampus, 420)


Vast majority of interneurons in the dentate gyrus and hippocampus have locally restricted target regions, lack spines, and are GABAergic. (Johnston; Hippocampus, 421)

Hippocampal interneurons with cell bodies in or near the pyramidal cell layer can be classified into three groups on the basis of their synaptic targets: axo-axonic cells, basket cells, and bistratified cells. (Johnston; Hippocampus, 423)

Axo-axonic cells synapse onto the initial segments of pyramidal neurons and thus exert a strong control over action potential initiation. (Johnston; Hippocampus, 423)

Basket cells synapse onto the somata of pyramidal neurons. Each basket cell can make multiple contacts onto a pyramidal neuron, forming what looks like a "basket" into which the soma sits. (Johnston; Hippocampus, 423)

Bistratified cells make synaptic contacts onto apical and basal dendrites of pyramidal neurons. (Johnston; Hippocampus, 423)

Mutual inhibitory connections among these interneurons. (Johnston; Hippocampus, 423)

Mutual inhibitory connections synchronize interneurons, producing oscillations at various frequencies, including theta (5 Hz) and gamma (40 Hz) frequencies. (Johnston; Hippocampus, 423)

Many GABAergic interneurons also contain and release neuroactive peptides. (Johnston; Hippocampus, 423)

Interneurons whose post-synaptic targets are exclusively other interneurons. (Johnston; Hippocampus, 423)

Basic circuitry of the hippocampal formation has been known since the time of Ramon y Cajal (1911). (Johnston; Hippocampus, 423)

Unidirectional progression of the Trisynaptic Circuit

Unidirectional progression of excitatory pathways that link each region of the hippocampal formation -- the trisynaptic circuit. (Johnston; Hippocampus, 424)

Entorhinal cortex is considered the starting point of the trisynaptic circuit since much of the sensory information that reaches the hippocampus enters through the entorhinal cortex. (Johnston; Hippocampus, 424)

Neurons located in layer II of the entorhinal cortex give rise to a pathway, the perforant path, that projects through (perforates) the subiculum and terminates both in the dentate gyrus and in the CA3 field of the hippocampus. (Johnston; Hippocampus, 424)

Dentate gyrus is the next step in the progression of connections, and it gives rise to the mossy fibers that terminate on the proximal dendrites of the CA3 pyramidal cells. (Johnston; Hippocampus, 424)

The CA3 pyramidal cells project heavily to other levels of CA3 as well as to CA1 the projection to CA1 is typically called the Schaffer collateral projection. (Johnston; Hippocampus, 425)

Information entering the entorhinal cortex from a particular cortical area can traverse the entire hippocampal circuit through the excitatory pathways and ultimately be returned to the cortical area from which it originated. The transformations that take place through this traversal are presumably essential for enabling the information to be stored as long-term memories. (Johnston; Hippocampus, 425)

The major input to the dentate gyrus is from the entorhinal cortex. (Johnston; Hippocampus, 427)

Subcortical inputs to the dentate gyrus

Subcortical inputs to the dentate gyrus originate mainly from the septal nuclei, supramamillaryagion of the posterior hypothalamus, and several monoaminergic nuclei in the brainstem, especially the locus coeruleus and raphe nuclei. (Johnston; Hippocampus, 428)

Dentate gyrus receives a particularly prominent noradrenergic input, primarily from the locus coeruleus. (Johnston; Hippocampus, 428)

Serotonergic projection originates from the raphe nuclei. (Johnston; Hippocampus, 428)

Many of the cells in the raphe nuclei that project to the hippocampal formation appear to be nonserotonergic. (Johnston; Hippocampus, 430)

Dentate gyrus receives a lighter and diffusely distributed dopaminergic projection that arises mainly from cells located in the ventral tegmental area. (Johnston; Hippocampus, 430)

Dentate gyrus does not project to other brain regions. Within the hippocampal formation, it only projects to CA3 via the mossy fibers. (Johnston; Hippocampus, 430)

Projections within the Hippocampus

CA3 pyramidal cells give rise to highly collateralized axons that distribute fibers both within the hippocampus (to CA3, CA2, and CA1), to the same fields in the contralateral hippocampus (the commissural projections), and subcortically to the lateral septal nucleus. (Johnston; Hippocampus, 431)

CA3 cells, especially those located proximally in the field, and CA2 cells contribute a small number of collaterals that innervate the polymorphic layer of the dentate gyrus. (Johnston; Hippocampus, 431)

All of the CA3 and CA2 pyramidal cells give rise to highly divergent projections to all portions of the hippocampus. The projections to CA3 and CA2 are typically called the associational connections, and the CA3 projections to the CA1 field are called the Schaffer collaterals. (Johnston; Hippocampus, 431)

Highly ordered and spatially distributed pattern of projections from CA3 to CA3 and from CA3 to CA1. (Johnston; Hippocampus, 431)

Each CA3 neuron makes contacts with many CA1 pyramidal cells. It has been estimated that a single CA1 neuron may be innervated by more than 5,000 ipsilateral CA3 pyramidal cells. (Johnston; Hippocampus, 432)

Projections from CA3 to CA1 terminate as asymmetric, axospinous synapses located on the apical and basal dendrites of the CA1 pyramidal cells. The sizes and shapes of the spines and presynaptic profiles in this region are quite variable and may be related to the physiological efficacy of the synapses in CA1. (Johnston; Hippocampus, 432)

CA3-to-CA3 associational and CA3-to-CA1 Schaffer collateral projections are both divergently distributed along the septotemporal axis. (Johnston; Hippocampus, 432)

Single CA3 and CA2 pyramidal cells give rise to highly arborized axonal plexuses that distribute to as much as 75% of the septotemporal extent of the ipsilateral and contralateral CA1 fields. (Johnston; Hippocampus, 432)

Total length of the axonal plexus from single CA3 neurons can be as long as 150-300 mm, and a single CA3 cell may contact as many as 30,000 to 60,000 neurons in the ipsilateral hippocampus.(Johnston; Hippocampus, 432)

The only sizable subcortical projection from CA3 is to the lateral septal nucleus.(Johnston; Hippocampus, 432)

Some CA3 fibers cross in the ventral hippocampal commissure to innervate the homologous region of the contralateral lateral septal nucleus.(Johnston; Hippocampus, 432)

Essentially all of the CA3 cells give rise to projections both to CA1 and to the lateral septal nucleus. (Johnston; Hippocampus, 432)

CA3 field receives inputs from the noradrenergic nucleus locus coeruleus. (Johnston; Hippocampus, 433)

Hippocampus ideal for studying Synaptic Actions

Highly structured and organized arrangement of synaptic pathways makes the hippocampus ideal for studying synaptic actions in vivo or in vitro. Single-shock electrical stimulations to the perforant path, mossy fibers, or Schaffer collaterals result in a characteristic sequence of excitation followed by inhibition in the appropriate target neurons. (Johnston; Hippocampus, 435)

Electrophysiological behavior of the different neurons in the hippocampus is variable. (Johnston; Hippocampus, 438)

Dentate granule and CA1 pyramidal neurons can fire repetitively at up to several hundred Hz. (Johnston; Hippocampus, 438)

CA3 pyramidal neurons tend to fire in short bursts of 5-10 action potentials. (Johnston; Hippocampus, 438)

Bursting properties of CA3 hippocampal neurons are thought to be important for explaining the seizure susceptibility of the hippocampus. (Johnston; Hippocampus, 438)

Frequency of action potentials declines or (accommodates)

A prominent feature of hippocampal neurons firing repetitively is that the frequency of action potentials declines or accommodates during the train, and there is a slow afterhyperpolarization (AHP) at the end of the train. (Johnston; Hippocampus, 438)

Both the frequency accommodation and the slow AHP result in part from the activation of potassium channels by the influx of calcium ions during the train. (Johnston; Hippocampus, 438)

Presynaptic mechanisms, including the quantal hypothesis for transmitter release and the role of presynaptic calcium, have been studied directly at both mossy fiber and Schaffer collateral synapses. (Johnston; Hippocampus, 438)

Dendritic Trees

Because excitatory synapses and some inhibitory synapses terminate on dendrites, the physiology and biophysics of synaptic transmission is complicated by the properties of dendrites. (Johnston; Hippocampus, 439)

Basic sequence of synaptic transmission begins with an action potential in the presynaptic axon that elicits Ca2+ influx into the bouton, and through a number of poorly understood steps, neurotransmitter is released into the cleft from transmitter-containing vesicles in the presynaptic terminal. (Johnston; Hippocampus, 439)

Transmitter molecules diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic neuron, opening ion channels. (Johnston; Hippocampus, 439)

Single boutons may have as few as 1 active zone in some Schaffer collateral boutons to as many as 37 active zones on some of the largest mossy fiber terminals. (Johnston; Hippocampus, 439)

A prominent theory is that one vesicle per action potential is released at each active zone with a mean probability of about 1 release every fourth action potential. (Johnston; Hippocampus, 439)

Vesicles can sometimes release their transmitter spontaneously in the absence of a presynaptic action potential. (Johnston; Hippocampus, 439)

Inhibitory neurons can fire repetitively at rates much higher than is typical for excitatory neurons. (Johnston; Hippocampus, 439)

Excitatory input to inhibitory interneurons may trigger a high-frequency train of action potentials in the interneurons, leading to longer-lasting transmitter release and a longer-lasting inhibition of the post-synaptic neuron than from the excitatory response. (Johnston; Hippocampus, 439)

Neurotransmitters in the Hippocampus

Major excitatory neurotransmitter in the hippocampus is glutamate. (Johnston; Hippocampus, 439)

Major inhibitory neurotransmitter in the hippocampus is GABA. (Johnston; Hippocampus, 440)

It was once believed that inhibitory synapses were primarily on the cell bodies of pyramidal neurons. There is now much evidence that GABAergic synapses occur both on the cell bodies as well as throughout the dendritic tree. (Johnston; Hippocampus, 442)

Neuromodulatory neurotransmitters acting pre- and/or postsynaptically that under some conditions can be considered inhibitory. These include norepinephrine, serotonin, dopamine, and neuroactive peptides. (Johnston; Hippocampus, 442)

Hippocampus Pathways

Perforant Pathway can be separated into two groups of fibers, the lateral and medial perforant paths. Opioid peptides influence the induction of longterm potentiation in the lateral perforant path. (Johnston; Hippocampus, 442)

Hilar Pathways -- physiology of the hilar region is poorly understood, compared with the rest of the hippocampus. (Johnston; Hippocampus, 442)

Mossy Fibers. Mossy fiber boutons are among the largest synapses of the mammalian central nervous system, surpassed only by certain synapses in the cochlear nucleus. At each bouton there are multiple active zones (up to 37) resulting in multiple release sites for neurotransmitter. The boutons contain large amounts of Zn2+ and opioid peptides that are co-released with the main neurotransmitter glutamate. (Johnston; Hippocampus, 442)

Mossy fibers terminate on the proximal dendrites of CA3 pyramidal cells. (Johnston; Hippocampus, 442)

Recurrent Pathways. One of the hallmarks of the CA3 region is the prominent, recurrent excitatory connections among the pyramidal neurons. This recurrent pathway is glutamatergic, and excitatory, and represents a form of positive feedback that makes the CA3 region inherently unstable. In combination with the intrinsic bursting properties of CA3 neurons; subtle increases in the ratio of excitation/inhibition in this region can result in epileptiform activity, which is characterized by spontaneous and synchronous, rhythmic firing among large numbers of neurons. (Johnston; Hippocampus, 443)

Schaffer Collaterals are probably the best-studied synaptic pathway in the hippocampus. Each Schaffer collateral axon synapses onto thousands of CA1 pyramidal neurons, but usually with only one or two synaptic contacts per neuron. (Johnston; Hippocampus, 443)

Axons of the CA1 pyramidal neurons also form a recurrent excitatory pathway that synapses back onto other CA1 neurons, although it is much sparser and weaker than that in CA3. (Johnston; Hippocampus, 443)

Synaptic Plasticity

Synaptic Plasticity - most of the excitatory synapses in the hippocampus exhibit various forms of use- or activity-dependent synaptic plasticity. (Johnston; Hippocampus, 443)

Short-term plasticities are facilitation, post-tetanic potentiation, and depression. They range in duration from hundreds of milliseconds to several minutes. (Johnston; Hippocampus, 443)

Long-term Plasticities -- There are several forms of synaptic plasticities at glutamatergic, excitatory synapses in hippocampus that have durations of from 30 min to hours, days, or weeks. They are called short-term potentiation and depression (STP and STD) and long-term potentiation and depression (LTP and LTD). (Johnston; Hippocampus, 445)

LTP was first described by Bliss and colleagues (Bliss and Lomo, 1973; Bliss and Gardner-Medwin, 1973) and is probably the most intensely studied of all the synaptic plasticities because of its presumed role in learning and memory. (Johnston; Hippocampus, 445)

LTP is typically induced by giving one or more high-frequency (25-200 Hz) stimulus trains to a synaptic pathway, such as the perforant path, mossy fibers, or Schaffer collaterals. This period of high-frequency stimulation trains is called the induction phase. (Johnston; Hippocampus, 445)

The induction phase of LTP is followed by an expression phase, during which a stimulus is amplified some 50-100%. Characteristically, an induction phase of only a few seconds to 1 min is much shorter than the subsequent expression phase, which may last up to several days. (Johnston; Hippocampus, 445)

Maximum duration of expression phase is difficult to ascertain, but LTP in hippocampus is unlikely to be permanent. (Johnston; Hippocampus, 445)

LTP has associative properties; synapses may exhibit LTP only when they are active at the same time as other synapses. These and other properties make LTP a candidate mnemonic device. (Johnston; Hippocampus, 445)

LTD represents a long-term depression of a synaptic response, induced by the low-frequency stimulation (1-5 Hz) of a synaptic pathway. LTD can last from 30 min to an hour or more. (Johnston; Hippocampus, 445)

Most theories for learning involve strengthening of specific synaptic pathways at the expense of others, and the existence of an LTD-like phenomenon has long been theorized. (Johnston; Hippocampus, 445)

At many synapses LTP and LTD are dependent on the activation of NMDA receptors. A requirement for the induction of LTP is that there must be a sufficient increase in the intracellular Ca2+ concentration near the stimulated synapses. This occurs by the influx of Ca2+ ions through NMDA receptors and/or voltage-gated Ca2+ channels. (Johnston; Hippocampus, 445)

At mossy fiber synapses and perhaps at lateral perforant-path synapses, LTP is facilitated by the release of opioid peptides. (Johnston; Hippocampus, 445)

STP and STD occur when the stimulation during induction is of insufficient intensity or duration to induce LTP and LTD. STP and STD have lower induction thresholds than their longer-term counterparts. (Johnston; Hippocampus, 446)

It is not clear whether STP and STD are just shorter-term versions of LTP and LTD or if they have separate mechanisms. Nonetheless, they share characteristics, such as a dependence on a rise in intracellular Ca2+ concentration in the postsynaptic neuron, and at some synapses, a requirement for NMDA receptor activation. (Johnston; Hippocampus, 446)



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