Renate Stauch

Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons

This study was designed to examine possible anatomical changes of thalamocortical circuits in schizophrenics. Previous immunocytochemical studies have shown that parvalbumin, a calcium-binding protein, occurs in thalamocortical projection neurons, but not in GABAergic interneurons in the anteroventral thalamic nucleus (AN). Using parvalbumin-immunocytochemistry we investigated the densities of thalamocortical projection neurons in the AN of schizophrenic cases (n = 12) and controls (n = 14). The densities of all neurons in the AN were estimated by Nissl-staining. The majority of thalamocortical projection neurons in AN were identified by parvalbumin-immunoreaction. Significantly reduced densities of thalamocortical projection neurons were estimated in the right (P = 0.003) and left AN (P = 0.018) in schizophrenic subjects. The densities of all neurons in right and left AN were also diminished in schizophrenics; however, these decreases did not reach statistical significance. The reductions of parvalbumin-positive thalamocortical projection neurons were not correlated with the length of disease, this finding supporting the neurodevelopmental etiology of structural abnormalities in schizophrenia.

Volumes of association thalamic nuclei in schizophrenia: a postmortem study

The major association thalamic nuclei, the mediodorsal nucleus (MD) and the medial pulvinar nucleus (PUM) are regarded as important parts of the circuits among association cortical regions. Association cortical regions of the frontal, parietal and temporal lobes have been repeatedly implicated in the neuropathology of schizophrenia. Thus, the aim of the present postmortem study was to investigate the volumes of association thalamic nuclei in this disease. The volumes of the whole thalamus (THAL), MD and PUM were measured in each hemisphere of brains of 12 patients with schizophrenia and 13 age-matched and gender-matched normal control subjects without neuropsychiatric disorders. Patients with schizophrenia exhibited significant volume reductions in both the MD and the PUM, the reductions being more pronounced in the PUM. The volume of the PUM in the left (-19.7%, P=0.02) and right (-22.1%, P=0.01) hemispheres was significantly reduced in the schizophrenia group. The volume of the MD was reduced in both hemispheres in the schizophrenia group. However, the volume reduction was only significant in the left hemisphere (-9.3%, P=0.03). Patients with schizophrenia also exhibited a decreased volume of the THAL in the left (-16.4%, P=0.003) and right (-15.2%, P=0.006) hemispheres. There were no significant correlations between thalamic volumes and duration of illness or age of the patients. In conclusion, the present data indicate volume reductions of association thalamic nuclei in schizophrenia. These anatomical findings are consistent with the view that schizophrenia may be associated with disturbances of association cortical networks. However, the findings of a substantial volume reduction of the THAL suggest that the volumes of additional thalamic nuclei may be also reduced in schizophrenia.

Volume deficits of subcortical nuclei in mood disorders A postmortem study.

AbstractStructural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case–control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders.Volumes of the striato–pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 μm whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Λ = 0.35, F20,56 = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( ƒ > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (ƒ > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.

Localization of neuregulin-1α (heregulin-α) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain

Abstract Using immunohistochemistry, Western blot analysis, and RT-polymerase chain reaction, we studied the distribution of neuregulin-1 splice variant α (NRG-1α) and one of its putative receptors, ErbB-4 tyrosine kinase, in human brain. In the pre- and perinatal human brain immunoreactivity was confined to numerous neurons, with the highest cell density found in cortical gray matter, hypothalamus and cerebellum. In the adult brain, single cortical gray and white matter neurons showed NRG-1α immunoreactivity. Occasionally, immunoreactive oligodendrocytes were observed. NRG-1α-expressing neurons were also found in the hypothalamus, hippocampus, basal ganglia and brain stem. Application of two antibodies recognizing α and β isoforms revealed a different distribution pattern in that many cortical and hippocampal pyramidal neurons were labeled. ErbB-4 immunoreactivity was expressed in both neurons and oligodendrocytes. Our data show that NRG-1α expression is lower in the adult human brain than in the developing brain, and, therefore, support a role for NRG-1α in brain development.

Volume and neuron number of the mediodorsal thalamic nucleus in schizophrenia: a replication study.

Previous neuropathological studies on the mediodorsal thalamic nucleus (MD) in schizophrenia have yielded conflicting results. While some studies suggested that patients with schizophrenia have a pronounced reduction of the volume and neuron number in the MD, more recent data have not found anatomical alterations in this thalamic nucleus. However, most studies have considerable methodological shortcomings. In the present study, we investigated the volume, neuron density and neuron number in the left and right MD in patients with schizophrenia (n=20) and normal control subjects without neuropsychiatric disorders (n=18). Patients with schizophrenia showed no significant difference in neuron density and total neuron number in the MD. Compared with the control group, patients with schizophrenia had a smaller MD volume in both hemispheres, a difference that approached significance in the left MD (-7.3%) when the whole brain volume was included as a covariate. No significant main group effect of diagnosis was found for the right MD volume. There were no significant correlations between MD volume, neuron density, total neuron number and the duration of illness or the age of the patients. Taken together, the present results suggest that schizophrenia is associated with a moderate volume reduction in the left mediodorsal thalamic nucleus, while the neuron density and the total neuron number are unchanged.

Strongly reduced number of parvalbumin-immunoreactive projection neurons in the mammillary bodies in schizophrenia: further evidence for limbic neuropathology.

Abstract:  The mammillary bodies (MB) are important relay nuclei within limbic and extralimbic connections. They are known to play important roles in memory formation and are affected in alcoholism and vitamin B1 deficiency. Their strategic position linking temporo‐limbic to cortico‐thalamic brain structures make the MB a candidate brain structure for alterations in schizophrenia. We studied 15 postmortem brains of schizophrenics and 15 matched control brains. Brain sections were stained either with Heidenhain‐Woelcke, glutamic acid decarboxylase (GAD), calretinin, or parvalbumin. We determined the volumes of the MB and performed cell countings using stereological principles and a computerized image analysis system. The volumes of MB do not differ between schizophrenics and controls. However, in schizophrenia the number of neurons as well as the resulting neuronal densities was significantly reduced on both sides (on left side by 38.9%, on right side by 22%). No changes were seen in the number of GAD‐expressing or calretinin‐containing neurons, whereas the number of parvalbumin‐immunoreactive MB neurons was reduced by more than 50% in schizophrenia. This cell loss (as a result of developmental malformation and/or neurodegeneration) points to a prominent involvement of the MB in the pathomorphology of schizophrenia. Parvalbumin‐immunoreactive GABAergic interneurons have been reported to be diminished in schizophrenia. However, in the MB parvalbumin labels a subpopulation of glutamate/aspartate‐containing neurons projecting mainly to the anterior thalamus. Thus, our data provide new evidence for impaired limbic circuits in schizophrenia.

The ventral lateral posterior nucleus of the thalamus in schizophrenia: a post-mortem study

The ventral lateral posterior thalamic nucleus (VLp) is an integral part of both the cerebello-thalamocortical and the basal ganglia-thalamocortical circuit. Although both circuits are thought to be involved in the pathophysiology of schizophrenia, the VLp has not yet been examined in schizophrenia. Using stereological techniques in the brains of eight patients with schizophrenia and in eight age- and sex-matched controls, we measured the nuclear volume of the VLp and obtained estimates of the total number of neurons in this nucleus. Whole brain volume did not differ between the schizophrenia group and the control group and was not correlated to the volume of the right VLp or left VLp. The volume (minus sign25%) and the total neuron number (minus sign27%) of the left VLp were significantly reduced in the schizophrenia group. There were no significant differences in the nuclear volume, neuron density and total neuron number in the right VLp between the schizophrenia group and the control group. There were no significant correlations between length of illness and the nuclear volume, neuron density and total neuron number of the left and right VLp. The present results suggest that the total neuron number of the left VLp is reduced in the schizophrenia group, which may reflect disturbed cerebello-thalamocortical and basal ganglia-thalamocortical circuits in this disease.

Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia.

Insulin-degrading enzyme (IDE) is a neutral thiol metalloprotease, which cleaves insulin with high specificity. Additionally, IDE hydrolyzes Abeta, glucagon, IGF I and II, and beta-endorphin. We studied the expression of IDE protein in postmortem brains of patients with schizophrenia and controls because: (1) the gene encoding IDE is located on chromosome 10q23-q25, a gene locus linked to schizophrenia; (2) insulin resistance with brain insulin receptor deficits/receptor dysfunction was reported in schizophrenia; (3) the enzyme cleaves IGF-I and IGF-II which are implicated in the pathophysiology of the disease; and (4) brain gamma-endorphin levels, liberated from beta-endorphin exclusively by IDE, have been reported to be altered in schizophrenia. We counted the number of IDE immunoreactive neurons in the dorsolateral prefrontal cortex, the hypothalamic paraventricular and supraoptic nuclei, and the basal nucleus of Meynert of 14 patients with schizophrenia and 14 matched control cases. Patients had long-term haloperidol treatment. In addition, relative concentrations of IDE protein in the dorsolateral prefrontal cortex were estimated by Western blot analysis. There was a significantly reduced number of IDE expressing neurons and IDE protein content in the left and right dorsolateral prefrontal cortex in schizophrenia compared with controls, but not in other brain areas investigated. Results of our studies on the influence of haloperidol on IDE mRNA expression in SHSY5Y neuroblastoma cells, as well as the effect of long-term treatment with haloperidol on the number of IDE immunoreactive neurons in rat brain, indicate that haloperidol per se, is not responsible for the decreased neuronal expression of the enzyme in schizophrenics. Haloperidol however, might exert some effect on IDE, through changes of the expression levels of its substrates IGF-I and II, insulin and beta-endorphin. Reduced cortical IDE expression might be part of the disturbed insulin signaling cascades found in schizophrenia. Furthermore, it might contribute to the altered metabolism of certain neuropeptides (IGF-I and IGF-II, beta-endorphin), in schizophrenia.

The volumes of the fornix in schizophrenia and affective disorders: a post-mortem study.

Structural and functional pathology of limbic structures including the hippocampus are frequently replicated in schizophrenia. Although the fornix is the main afferent system of the hippocampus to the septal nuclei and the hypothalamus (especially the mammillary bodies), relatively few studies have investigated structural changes of the fornix in schizophrenia. We measured the volume of the fornix in post-mortem brains in 19 patients with schizophrenia, 9 patients with bipolar disorder, 7 patients with unipolar depression, and 14 control subjects by planimetry of serial sections. The volumes, the mean cross-sectional areas, and the anterior to posterior distances of the fornix did not differ among patients with schizophrenia, bipolar disorder, unipolar depression, and control subjects. No lateralization existed between the right and the left fornices in among patients in the diagnostic groups and the control subjects. The fornix does not show morphometrical abnormalities in patients with schizophrenia, bipolar disorder and unipolar depression compared with control subjects, which might indicate that the fornix is not a primary focus of structural changes in these diseases.

Increased density of GAD65/67 immunoreactive neurons in the posterior subiculum and parahippocampal gyrus in treated patients with chronic schizophrenia.

Abstract Objectives. Alterations of glutamic acid decarboxylase (GAD) play a crucial role in schizophrenic pathology. While GAD has been studied in several brain regions, its expression in the posterior hippocampus formation has not been investigated in schizophrenia. Methods. We studied the brains of 17 patients with chronic schizophrenia and 15 controls. Using the optical dissector method we counted GAD65/67 immunoreactive neurons and pyramidal cells in the posterior hippocampus, subiculum, and parahippocampal gyrus, and measured the cortical thickness in posterior subiculum and parahippocampal gyrus. Patients had received typical neuroleptics for the mean of 20.8 years. Results. In the patients we observed a significant increase of GAD immunoreactive neurons in the subiculum (left/right P = 0.004) and the parahippocampal gyrus (left P = 0.001, right P = 0.006). The hippocampus showed no or only subtle trends towards higher GAD densities. The density of pyramidal neurons and cortical thickness did not differ between the groups. A significant association between GAD density and the duration of illness was found in women with schizophrenia. Conclusions. The current data on GAD65/67 indicates a dysregulation of the GABAergic system in schizophrenia patients that may be associated with cognitive decline. However, a long term effect of neuroleptics on the GABAergic system cannot be excluded.