Hippocampal neuroanatomy in schizophrenia.

Reducing the size of the hippocampus in schizophrenia was found in a study of autopsy brain by a number of authors in the 80s, although other researchers could not confirm these data. This may be due to the fact that the decrease in the volume of the hippocampus in absolute terms is very small and is subject to the influence of clinical and demographic factors.

The data concerning the number of glutamatergic pyramidal neurons and cytoarchitecture of the hippocampus in schizophrenia are also rather contradictory, as reflected in the review by D. Weinberger. On the one hand, both the decrease in the numerical density of pyramidal neurons in the hippocampus during schizophrenia and its local increase were revealed, on the other hand, no such significant changes were found. Some publications have described the disorientation of pyramidal neurons in some areas of the hippocampus in schizophrenia, which has not been confirmed by other researchers. Data on the reduction of the size of the bodies of pyramidal neurons in the hippocampus, obtained by a number of researchers, also did not find confirmation in subsequent studies. The reason for such contradictions, in addition to the above, may also be errors in the methodological approach. We are talking about the absence in quantitative studies of the stereological approach, which allows to avoid distortion of the results associated with the effect on the studied parameters of the thickness of the slices, the size and distribution of the studied cells, etc. Recent studies performed using stereological methods on large groups of schizophrenic patients and mentally healthy people showed not only the absence of changes in the size and number of pyramidal neurons of the hippocampus, but also in the volume of the hippocampus or its regions.

Nevertheless, due to the use of the Golgi method, it was possible to reveal a decrease in the numerical density of the spines and a violation of the arborization of the dendritic tree of the pyramidal neurons of the subicle and the granular neurons of the dentate fascia. Immunocytochemical studies using antibodies to a specific dendritic marker – microtubule-associated protein 2 (MAP2) and the subunits of the kainate receptor GluR5,6,7 confirmed these findings. Although data on immunoreactivity and mRNA expression for the MAP2 dendrites marker are rather contradictory, these findings, together with the results of classical neuromorphological studies, indicate a significant reduction in the dendritic tree of the pyramidal neurons of the hippocampus in schizophrenia. The significance of this fact is determined by the fact that, as is known, the size of the processes is closely related to the size of the neuron body. Therefore, the question of reducing the size of the pyramidal neurons of the hippocampus in schizophrenia cannot be considered finally resolved.

As for the inhibitory GABAergic interneurons, which, along with pyramidal neurons, are the most numerous in the hippocampus, a decrease in their number in schizophrenia was first detected in the CA2 region of the hippocampus using neurohistological techniques of F. Benes et al. In the future, these data were confirmed by methods of immunocytochemistry and in situ hybridization. According to S. Heckers et al., the density of neurons containing the mRNA of the two isoforms of the main enzyme for the synthesis of GABA-glutamate decarboxylase (isoform 65 kilodalton – GD65 and isoform 67 kilodalton – GD67) was reduced in the hippocampus with schizophrenia by an average of 10%, with mRNA expression for both isoforms of the enzyme did not change. However, other authors have found a significant decrease in both the expression and the protein content of GD67- (but not GD65-) enzyme isoform in the hippocampus in schizophrenia. When interpreting these data, one should take into account that the authors of the relevant works did not reveal the effect of neuroleptic therapy on the expression of HD.

It has also been established that the number of interneurons containing parvalbumin (but not calretinin) decreases in the hippocampus in schizophrenia. As mentioned above, parvalbumin-containing neurons are a special subclass of inhibitory interneurons that innervate the bodies of pyramidal neurons and the initial segments of their axons. It should be emphasized that the lack of interneurons, including parvalbumin, in schizophrenia is not a phenomenon inherent only in the hippocampus, it was also detected in the prefrontal cortex. On the other hand, the results of immunocytochemical determination of the number of parvalbumin-immunoreactive neurons can be significantly influenced by the level of expression of the antigen. In schizophrenia in the hippocampus, a decrease in parvalbumin expression has been shown. Although the use of histological methods revealed a decrease in the number of inhibitory interneurons in schizophrenia only in the CA2 region of the hippocampus, this contradiction may be explained by the fact that parvalbumin neurons constitute only a part of the population of hippocampal interneurons. In this regard, it should be noted that there is a decrease in the expression of not only parvalbumin, but also Kalbindin, mainly in the CA2 region of the hippocampus. Although it was not possible to detect in schizophrenia a decrease in the numerical density of Kalbindin-immunoreactive neurons in the hippocampus, these data are consistent with the previously described selective deficit of interneurons in the CA2 region of the hippocampus.

Unfortunately, data on the effect of antipsychotic drugs on morphology and the number of pyramidal neurons in the hippocampus are not available. It was found that the expression of the dendritic marker MAP2 in the hippocampus of experimental animals increases with the introduction of neuroleptics. Experimental studies of the possible effect of antipsychotic therapy on the number and size of GABAergic neurons in the hippocampus or its individual sectors did not reveal changes in these parameters in response to a 3-week introduction of haloperidol or olanzapine.
Thus, data from neuroanatomical (histological) studies of the hippocampus in schizophrenia indicate more likely quantitative changes in cytoarchitectonic parameters that are not reflected in the overall histological pattern of the structure. There were no significant changes in the total number of hippocampal neurons in schizophrenia, with the exception of one of the subpopulations of GABAergic interneurons. However, the data presented on the reduction of the dendritic tree of the pyramidal neurons of the hippocampus suggest disorders in schizophrenia of the interneuronal connections, which is, according to some authors, the main component of the pathology of the hippocampus in this disease.

Lifetime studies of the hippocampus in schizophrenia

There are numerous studies of the hippocampus in schizophrenia, which were performed using modern methods of computer x-ray and magnetic resonance (MPT) tomography. The findings suggest a decrease in the volume of this structure in patients with schizophrenia compared with healthy people. Sensitive modern methods of multidimensional brain mapping revealed that in some cases, in the absence of volume changes, there is a deformation of the hippocampus, manifested in a decrease in the curvature of its posterior section.

It is important to emphasize that both the reduction in the volume of the hippocampus and the changes in its shape were observed in patients who first became ill and did not receive antipsychotic therapy, as well as in their mentally healthy relatives. This suggests that these changes are not brought about by disease or therapy, and, most likely, are an important feature of the brain in schizophrenia. This interpretation is supported by the presence of general morphological features of the hippocampus (volume reduction) in schizophrenia and schizoaffective disorders. Some authors suggest that a decrease in the volume of the hippocampus in schizophrenia may be the basis of a predisposition to the development of this disease.

Some authors, however, failed to detect a decrease in the volume of the hippocampus in schizophrenia. Naturally, these contradictions have led to attempts to identify their possible causes. This was done, in particular, M. Nelson et al. based on the analysis of a large number of papers published before 1998. They concluded that the constant, although small (on average, 5%) deficit of the hippocampus is a characteristic feature of schizophrenia, the main reason for the contradictions is the use of inadequate statistical methods, especially in cases where a small amplitude of change is combined with significant individual variability. Other researchers believe that the cause of the contradictions may be the clinical heterogeneity of schizophrenia itself and, accordingly, differences in patient samples. Moreover, some authors have noted the link between the decrease in the volume of the hippocampus and some psychopathological phenomena — thought disorders and auditory hallucinations. In addition, the available data do not allow us to conclude unambiguously whether the reduction of the hippocampus progresses with an increase in the duration of the disease. Attention is drawn to the fact that atypical antipsychotics (olanzapine) can cause an increase in the temporal lobe of the brain, thereby masking the decrease in the size of the hippocampus.

Of particular interest are lifetime changes in the function of the hippocampus in schizophrenia. The corresponding data were obtained using magnetic resonance spectroscopy (MRS) with mapping and positron emission tomography (PET) with the registration of regional cerebral blood flow.

In MDR, it was possible to detect dysfunction of the glutamatergic neurons of the hippocampus during schizophrenia in vivo, as indicated by a decrease in the content of N-acetyaspartate (NAA) in it, including in patients who did not receive neuroleptic therapy. NAA is known to be a neuronal marker that serves as an indicator of both the deficiency of glutamatergic neurons and their dysfunction. However, a decrease in the NAA signal in the hippocampus in schizophrenia is more a result of dysfunction of glutamatergic neurons than their deficit, since these changes were detected in the absence of changes in the volume of the hippocampus and were not accompanied by changes in the choline signal, an indicator of the state of cell membranes. Experimental studies confirm that the suppression of the intensity of the NAA signal may correlate directly with a decrease in the functional activity of glutamatergic neurons even in the absence of their deficiency. The severity of NAA-signal suppression in the hippocampus in schizophrenia, according to a number of authors, correlates positively with both the severity of positive symptoms (delusions, hallucinations, etc.) and the severity of memory and attention disorders.

In PET studies, it was shown that a decrease in blood flow in the hippocampus in patients who did not receive neuroleptic therapy for 2–3 weeks also correlates with the severity of positive symptoms. The suppression of the involvement of the hippocampus in the implementation of tasks associated with verbal memory has also been shown previously. The authors attribute this specific cognitive deficit to manifestations of psychosis, such as auditory hallucinations and disorganized speech. However, a comparison of groups of patients separated by the presence or absence of a pronounced mental defect in them revealed a similar suppression of the activation of the hippocampus when solving problems associated with the reproduction of new words. These data may indicate that the dysfunction of the hippocampus in schizophrenia, associated with the implementation of cognitive processes, can be universal and underlie a wide range of symptoms of the disease in question.

It remains unclear whether changes in the structure of the hippocampus, which were detected during post-mortem studies, can be a cause of disorders in the size and shape of the hippocampus observed at the MRI level. Obviously, this relationship may not be direct. In the already classic works of R. Sapolsky et al. showed that the impact of chronic stress on primates causes pronounced changes in the cytoarchitecture of the hippocampus, associated with the loss of neurons and gliosis, but is not accompanied by significant in vivo changes in the volume of the hippocampus. On the other hand, it was shown that a decrease in the volume of the hippocampus is characteristic of Alzheimer’s disease, accompanied by marked neurodegenerative changes in it  However, with other mental illnesses that are accompanied, like schizophrenia, by minimal cytoarchitectonic disorders in the hippocampus, intravital MRI studies show different directions for changes in the volume of this structure. Thus, in manic-depressive psychosis, the volume of the hippocampus increased or did not change, whereas in depression, a decrease in the volume of the hippocampus, often depending on the age of onset of the disease, was shown. In schizophrenia, neuroendocrine disorders of some patients, associated with polydipsia and hyponatremia, may have a certain effect on the lifetime reduction of the hippocampus.

Thus, data from in vivo studies indicate that a decrease in volume and / or a change in the shape of the hippocampus, as well as a disruption of its functional activity, may be an important feature of the brain in schizophrenia. Although the severity of structural and functional disorders of the hippocampus is associated mainly with the predominant, mostly positive symptoms, the basis for this relationship may be a violation of the cognitive functions determined by the hippocampus. Therefore, we dwell on them in more detail.

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