Pathology of the Hippocampus in schizophrenia. Part 1

The hippocampus is a key element in the organization of subjective perception-action, ensuring the switching of conscious attention.
Hippocampal neurons serve all possible emotional contexts, because specific to all types of neurotransmitters.

This means that at different concentrations of neurotransmitters, only those connections in the hippocampus that are specific to these neurotransmitters will be included, which, at this level, ensures that the perception-response style is highlighted.

The pathology of the hippocampus in schizophrenia has begun to attract the particular attention of researchers over the past two decades. This is primarily due to the progress in the development of methods for intravital studies of the brain (computer, magnetic resonance imaging, etc.), allowing to identify violations of the structure and functions of the hippocampus in the brain of patients with this disease. In addition, these data have given particular importance to the results of morphological and neurochemical studies of autopsy brain, which revealed structural and functional changes in the hippocampus during schizophrenia. The hippocampus attracts the attention of researchers also due to the fact that its structure and functional organization are well studied, which allows you to come closer to establishing parallels between the clinical manifestations of the disease and its pathology.
This review presents a modern understanding of the structure and functions of the hippocampus in terms of studying its role in the pathogenesis of schizophrenia according to the literature of the past two decades.

The main sections of the review contain the results of intravital structural and functional studies of the hippocampus in schizophrenia; data from neurochemical studies concerning predominantly alterations of glutamate and GABAergic neurons of the hippocampus in schizophrenia; analysis of evidence of synaptic contact impairments, including the results of synaptic marker studies and ultrastructural research data. These sections are prefaced with basic information about the anatomy and physiology of the hippocampus.
Structure and main functions of the hippocampus
The hippocampus enters the hippocampal formation, which includes, in addition to it, the dentate fascia, subicle, presubiculum, and entorhinal cortex, and is a key structure of the limbic system of the brain.

The hippocampus itself (or Ammon’s horn) is a dense ribbon of cells that stretches in the anteroposterior direction along the medial wall of the lower horn of the lateral ventricle of the brain. The main nerve cells of the hippocampus are represented by pyramidal neurons and polymorphic cells, most of which are intercalated neurons with processes that do not extend beyond the limits of the hippocampus.

Being an ancient cortex, the hippocampus consists of 3 main layers: a polymorphic layer (stratum oriens), a layer of pyramidal neurons (stratum pyramidale) and a molecular layer (stratum radiatum and stratum lacunosum-muslare)

The layer lying on the ventricular surface, alveus, consists mainly of horizontally myelinated axons of the pyramidal neurons of the hippocampus. The basal dendrites and initial axon segments are located in the stratum oriens. This is followed by a layer of pyramidal neurons, and then a stratum radiatum, containing the trunks of the apical dendrites, and the stratum lacunosum-muslare, where the terminal terminal and terminal branches of the apical dendrites are located. The precise organization of the cytoarchitecture of the hippocampus is preserved throughout its front-uterine course, which suggests its laminar organization.

The peculiarities of the cytoarchitecture of the pyramidal layer of the hippocampus served as the basis for its division into 4 main fields, oriented in the mediolateral direction and designated as CA1 – CA4. The main fields of the hippocampus itself are CA1 and CA3. The CA1 field is distinguished by small pyramidal neurons that are tightly arranged in 2 layers, the cells of this layer in the CA3 region are very large, not so densely arranged. Apical dendrites of the CA1 pyramids run at a considerable distance from the cell as a single stem and do not have large spiny outgrowths. Powerful apical dendrites of the CA3 pyramids of the region give bifurcation near the cell body and are covered with giant spike outgrowths (thorny excrescences). These giant spines of the CA3 pyramidal neurons form synaptic contacts with axons of granular neurons of the dentate fascia, mossy fibers. Axons of the CA3 pyramidal neurons give the so-called Schaffer collaterals in contact with the apical dendrites of the CA1 pyramids. The above links are the two main associative pathways of the hippocampus, connecting together its main elements, and constitute the so-called trinsynaptic pathway. Both the mossy fiber system and the main afferent entrance of the dentate fascia (perforating path) are characterized by strict topical organization. Thus, the hippocampus can be represented as a set of consecutive morphofunctional segments that can function relatively independently.

Laminar organization is also characteristic of the terminal fields of afferent inputs and commissural connections with the contralateral hippocampus [68]. The most important afferent inputs, from the septum and the entorhinal cortex, end up mainly in the CA3 region of the hippocampus, whereas the pyramidal neurons of the CA1 region receive the afferent input directly from the entorhinal cortex. The entorhinal cortex in turn receives afferent inputs from the limbic cortex and polymodal associative zones of the neocortex. Direct efferent connections from the hippocampus to the temporal region of the neocortex and the prefrontal cortex were also detected. Septum is connected to the hippocampus by bilateral ties and is an extremely important relay link on the paths between the hippocampus and the structures of the brain stem and the hypothalamus. Other efferent pathways of the hippocampus are directed mainly to the structures of the limbic circle. Thus, the CA3 region of the hippocampus is the point of convergence of information flows from the associative cortex and phylogenetically ancient structures of the brain stem.

The basis of the functioning of the hippocampal neural ensembles is glutamatergic neuromediation, since both the pyramidal neurons and the granular cells of the dentate fascia are glutamatergic. However, almost all known neurotransmitter systems play a significant role in the regulation of the functional activity of the hippocampus. GABA and cholinergic afferents are important modulating inputs from septum. The CA3 region of the hippocampus receives direct inputs from the noradrenergic blue spot and serotonergic suture nuclei. The entrance from the nuclei of the reticular formation of the brainstem is carried out indirectly through the cholinergic nuclei of the forebrain.

Inside the hippocampus, the brake control of glutamatergic pyramidal neurons is carried out by polymorphic intercalated neurons, most of which are GABAergic. The latter are subdivided into several subtypes according to the content of calcium-binding proteins in them: parvalbumin-, calbindin- and calretinin-containing interneurons. Parvalbumin neurons innervate mainly (but not exclusively) the bodies of pyramidal neurons]. A special subclass of parvalbumin-containing neurons, the so-called “candelabra cells”, innervate the initial axonal segments of the pyramidal cells of the hippocampus. Kalbindin-containing neurons form synaptic contacts primarily on the proximal apical dendrites of pyramidal cells. Calretinin-containing interneurons mainly specialize in inhibitory control of other GABAergic neurons.

As already mentioned, the CA3 region occupies a special place in the structural and functional organization of the hippocampus, since it is precisely the neurons of this hippocampus region that receive the main information flows from the higher associative cortical zones, as well as from the stem and subcortical structures of the brain. The functional organization of neural ensembles in the CA3 region of the hippocampus has a number of specific features. The CA3 pyramidal neurons are connected to each other through a set of reciprocal links, with the result that each of them is able to influence the discharge of many other neurons. The GABAergic CA3 interneurons also receive a glutamatergic stimulating entry from the pyramidal neurons of this region and from the collaterals of mossy fibers (axons of the granular neurons of the dentate fascia) that innervate the apical dendrites of the pyramidal neurons. Thanks to this system of connections, the inhibitory neurons of the hippocampus are capable of performing both direct and reverse inhibition of pyramidal neurons. This complex network can control pyramidal neurons and provide the time structure needed to coordinate the activity of hippocampal neuronal ensembles. Since inhibitory interneurons modulate both afferent inputs and efferent activity and the excitability of pyramidal glutamatergic neurons, they are able to synchronize large cell populations. It is believed that, being the main target of the subcortical pathways, it is inhibitory interneurons that are able to exercise motivational, emotional, and autonomous control of the activity of the hippocampus. Braking control of glutamatergic pyramidal neuron activity is also the basis of memory acquisition and reproduction processes.

The exclusive role of the hippocampus in the processes of memory and learning in humans and animals is currently a proven fact, largely due to the work of domestic researchers. After the emergence of such methods as recording the electrical activity of single neurons, local microdestruction, etc., it became possible to study the role of individual areas and even individual types of hippocampal neurons in the processes of acquisition, storage and reproduction of memory. Summarizing the data of numerous clinical observations of patients with a destroyed hippocampus, Vinogradov concluded that the destruction of the hippocampus leads to violations of the so-called general (supmodal) memory factor.

To understand the role of the hippocampus in brain activity, it is important to emphasize that the hippocampus has powerful links with the associative cortex. Neocortical-limbic projections from individual sensory areas of the cortex are duplicated by connections from the higher convergence areas of all modalities (the lower tempered region and the upper part of the superior temporal gyrus in the posterior part of the hemispheres, as well as the frontoorbital cortex, arcuate sulcus and frontal poles in the front part of them). The posterior associative and convergent regions are believed to be associated with gnosis, i.e. “Objective” reception of external information, its processing and storage, whereas the pre-frontal areas – not only with praxis, but also with a subjective attitude to external information, to their own actions and their results. Such a two-way connection of these areas with the limbic system is necessary for the normal functioning of the fixation system of the new experience and the reproduction of the old.

Thus, the hippocampus is a structure that plays a large role in the implementation of cognitive functions. In this regard, it attracts the attention of researchers in cases of cognitive deficits, especially in Alzheimer’s disease and other neurodegenerative diseases, as well as in the development of such deficits in endogenous psychosis, including schizophrenia.

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