Excrescences are unique dendritic postsynaptic structures of the hippocampal formation. Only CA3 pyramidal neurones and hilar mossy cells possess these complex dendritic structures. Dendritic excrescences have so far only been investigated in rabbit, rat and rhesus monkey. Applying a Golgi impregnation method optimized for human brain tissue, we describe the detailed morphology of excrescences of CA3 pyramidal neurons of man. Human thorny excrescences possess a thin and single spine neck and multiple spine heads (4 on average, sometimes more than 10). Human cluster excrescences sit upon the dendrite with a broad stem, and exhibit a "papilloma-like" surface. Some human CA3 pyramidal neurons seem to possess markedly longer spine necks and larger spine heads compared to human neocortical pyramid cells; they were named long-neck spines. Thorny excrescences, cluster excrescences and the newly described long-neck spines can also be found on the dendritic main stem of human CA3 pyramidal neurons.CA2 pyramidal neurons neither possess these long neck spines nor thorny or cluster excrescences. Thus, the unique excrescences of CA3 pyramidal neurones seem to be another criterion for a demarcation between the CA3- and CA2 region of the human hippocampus.

Several structural deviances in the brain in "endogenous psychoses" have been described over the last decades. The enlargement of the lateral ventricles and the subtle structural deficits in temporobasal and orbital frontal structures (hypofrontality) are reasonably well established in the majority of schizophrenic patients. We examined the cytoarchitecture of these important central structures, namely the entorhinal region and the orbitofrontal cortex (Brodmann area 11), which have been under meticulous investigation in our laboratories over the last few decades. In a new series of schizophrenic patients and normal controls, we made serial cuts of the whole rostral entorhinal cortex on both sides. For this report, we selected two cases with very different psychopathologies, and present the serial cuts through both hemispheres and the malformations found. We report on the differing magnitude of the heterotopic malformations (for definition see page 103), either bilaterally or unilaterally.

Schizophrenia has been suggested to be a neurodevelopmental disorder, and nitric-oxide-synthase (NOS)-positive neurons were shown to be involved in distorted cortical development in schizophrenia. Here we investigated whether nitrinergic neurons in the striatum of schizophrenic patients also display abnormalities regarding distribution or morphology. To do so, postmortem putaminal sections of schizophrenic subjects were examined by means of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) staining and NOS immunohistochemistry. NOS-positive neurons were counted and analyzed morphologically. Abnormalities regarding morphology or number of NOS-containing neurons could be found in the putamen of schizophrenics (n = 3), but not controls (n = 5). Neurons were either of abnormal size and branching pattern, or they were markedly reduced (130 ± 44 vs. 54 ± 62 NADPHd-positive somata/mm3 putamen; p < 0.0001). Striatal nitrinergic interneurons might thus be involved in the pathogenesis of at least some forms of schizophrenia. Studies on larger samples are however needed to further corroborate this finding.

We demonstrate here for the first time the formation of vascular anastomoses in the human neocortex. The orbitofrontal cortex (OFC) of the perinatal human brain is structurally immature, so that the maturation of neurons, neuroglia and intracortical capillaries can be conveniently studied by comparison with these elements in motor and striatal cortex of the same brain. In OFC of the perinatal human brain, indication of prominent anastomosis formation in the upper layers (lamina II and III) is observed. Golgi silver impregnation and electron microscopic techniques were employed to demonstrate individual stages of vascular anastomosis development. Along with capillary angiogenesis, vascular anastomosis formation is of major importance for the ontogenesis of neuronal and glial elements of the CNS, particularly with respect to optimal metabolic support of structural elements of the mature brain. In the neocortex of the adult human brain, a characteristic three-dimensional capillary angioarchitecture is observed, contrasting with the two-dimensional arrangement in the immature perinatal cortex. Abnormal OFC angioarchitecture was also found in 14% of histomorphologically investigated brains from persons with endogenous psychoses. For the pathogenesis of functional disorders of the human brain, including endogenous psychoses, knowledge about the processes of structural maturation of neurons and neuroglia, but also of capillary architecture, is essential.

Neurons in the human striatum have been divided into five or seven different types, respectively. To further characterize these interneurons, we investigated the putamen of five brains by means of NADPH-diaphorase staining and compared our results to previous classifications in man. The NADPH-diaphorase method is selective for nitric oxide synthase (NOS); in the human striatum, predominantly interneurons were stained. NADPH-diaphorase positive neurons were then further examined. They showed clear morphological differences and could be classified into 12 different types, which only partially corresponded to previously described neuron types. Thus, we suggest at least three novel types of neostriatal interneurons. Furthermore, a special class of large neurons thought to be efferent in nature, stained NOS-positive.

In the hippocampal formation of schizophrenics, the detailed morphology of Golgi-impregnated granule cells was examined. These granule cells of the dentate gyrus are interposed between the rostral entorhinal cortex and the hippocampus proper. In these limbic regions significant cytoarchitectural alterations in schizophrenics are reported, giving rise to the concept of a prenatal limbic maldevelopement in schizophrenia. Compared to controls, the frequency of dentate granule cells with basal dendrites was significantly increased in schizophrenics [43% (±3)] vs. [22% (±2) in the control group]. In epilepsy, dentate granule cells of epileptic patients also develop basal dendrites, which is explained as an adaptive process of plasticity. Similarly, the hippocampal alterations described in schizophrenics could be the sequela of primary entorhinal cytoarchitectural alterations. Since the increase in basal dendrites seems to reflect a process of continuous plasticity, suggesting an increased rate of postnatal granule cell generation, the synthesis of a prenatal limbic maldevelopement with an ongoing process of plasticity might, therefore, supersede the hypothesis of a neurodegeneration in schizophrenia.

We report on structural variability of granule cells in the human dentate gyrus. Granule cells with basal and recurrent dendrites are a normal finding in the human brain. We detect 28.3% granule cells with basal dendrites in non-psychiatrically ill humans compared to rats (2%) and primates (10%). This can be seen as an indication for the higher phylogeny of the human brain. In addition we find a significantly higher incidence of granule cells with basal dendrites (45.7%) in brains of schizophrenic patients. Whereas drug influences during lifetime cannot fully be excluded, we tend to interpret this finding as a plastic reaction to prenatal developmental malformations of the impinging rostral entorhinal region.

The last decades have revealed several structural deviances in patients with so called "endogenous psychoses". Reasonably well established are the enlargement of the lateral ventricles and subtle structural deficits in temporobasal and orbital frontal structures (hypofrontality) in a majority of schizophrenic patients. It is the aim of this investigation to examine the cytoarchitecture of these important central structures, namely the entorhinal region and the orbitofrontal cortex (Brodmann area 11) which have been under meticulous investigation in our laboratories over decades (for review: Beckmann, 2000).

The nucleus accumbens, an integral and important part of limbic and prefrontal cortico-striato-pallidal-thalamic circuits, is involved in several cognitive, emotional and psychomotor functions altered in schizophrenia. In animal models, developmental disturbances within the entorhinal cortex and the hippocampus induce a dysregulation of inputs to the nucleus accumbens resulting in behavioral abnormalities which point to psychotic psychopathology. Nonetheless, due to the complex neuroanatomy of the human ventral striatum hardly any morphometric data on the nucleus accumbens are available.A postmortem stereological investigation of the nucleus accumbens was performed in complete brains of 9 male schizophrenics and 9 male controls between the ages of 46 and 64. Complete serial coronal slices of both hemispheres were stained with a modified Nissl-technique. Tissue shrinkage after staining and embedding was corrected for both individual and regional shrinkage. Based on recent precise delimitations of the human ventral striatum, in vivo hemisphere-adjusted volumes of the nucleus accumbens (volume densities) and absolute accumbal volumes were calculated applying the Cavalieri-estimator.In schizophrenics, mean hemisphere-adjusted volumes of the nucleus accumbens were significantly increased on both sides (right accumbens: p = 0,005**; left accumbens: p = 0,016*). Hemispherical volumes and volumes of the nucleus accumbens were significantly correlated in both groups (p = 0,02*).Most likely, this increase in volume of the ventral striatum reflects a decrease in naturally occuring cell death following prenatal cortical neurodevelopmental disturbances.

A search for Drosophila mutants with phenotypes similar to human diseases might help to unravel evolutionary conserved genes implicated in polygenic human disorders. Among these are neurodegenerative diseases, characterized by a late onset disturbance of memory, synaptic and glial pathology, structural brain impairments and altered content of the intermediates of the kynurenine pathway, the modulators of glutamate excito- and oxidative toxicity. This pathway is conserved in insects, in rodents, and in humans. We tested the Drosophila mutants cardinal (3-hydroxykynurenine excess) and cinnabar (kynurenic acid excess) for age-dependent changes in memory, synaptic pathology, structural brain plasticity and glial immunoreactivity. The mutant cardinal demonstrated a decline in learning and memory from the 12th to the 29th day of life in a paradigm of conditioned courtship suppression. Memory decline was accompanied by a sharp decrease in immunoreactivity to the synaptic cysteine string protein, and alterations in volumetric parameters of the mushroom bodies, the brain structures implicated in memory.

Despite a considerable number of investigations revealing the prefrontal cortex (PFC) to be a major site of pathological changes in schizophrenia, the neuronal basis of these alterations is still unknown. We used a 3-D image analysis technique to investigate the dendritic arborization of Golgi-impregnated prefrontal pyramidal neurons in schizophrenic patients and controls. While the apical dendrites were found to be unchanged in schizophrenics, the basilar dendritic systems were markedly reduced in the patient group. A segment analysis showed that the observed alterations were mainly confined to distal dendritic segments. The dendritic changes are likely to be associated with specific dysfunctions of prefrontal circuitry and point to the pathogenetical relevance of pre- and perinatal disturbances of PFC maturation in schizophrenic patients.

Axon cartridges are the specific terminal structures of GABAergic inhibitory chandelier interneurons. Cartridges form axo-axonal synapses with local projection neurons, thus modulating the neuronal output of diverse brain areas. In order to examine the distribution of cartridges, the anterior cingulate cortices from the brains of schizophrenic patients and control persons were examined with an antibody against parvalbumin. Axon cartridges were mainly located in layers V and VI. In our study, schizophrenic patients showed a significantly higher density of axon cartridges than controls. These findings add new evidence for disturbances of the circuitry of the anterior cingulate cortex in schizophrenia implicating that there may be an elevated inhibitory influence on the cortical output of this brain region.

A comprehensive neuropathology of schizophrenic psychoses has not yet been established. According to the findings of clinical investigations, neurohistological studies mainly focused on limbic structures, the prefrontal cortex and the anterior cingulate cortex. The results of morphometric and stereological studies based on the classical neuropathological techniques are controversial and point to the necessity for a differentiated characterization of the morphological features of neurons. Therefore, methods of neurobiological fundamental research are employed for the detailed demonstration of the different neuron types that constitute cortical circuits. Using these techniques, the schizophrenic cortex is shown to contain a variety of characteristic alterations which are discussed in the light of hypotheses favoring a maldevelopmental pathogenesis of schizophrenic psychoses which can be looked upon as neuronal system disorders.

Previously, immunohistochemical methods were primarily used to detect and provide indirect evidence on the composition of Lewy bodies, the pathological hallmark of Parkinson's disease. This was chiefly because there are very few procedures that describe the isolation of these structures. We report here a relatively simple method that we have developed for the exclusive isolation of Lewy bodies from brain tissue. The isolation of the Lewy bodies and subsequent evaluation of their components may furnish an insight into their role in the neurodegenerative mechanism(s) operating in the spectrum of Lewy body disorders.

The density of hippocampal adenosine A1 receptors was measured in autopsy samples of six patients with dementia with either Alzheimer (three) or sclerosis type pathology (three) in hippocampus and six control patients. Kinetic parameters (Bmax and KD) were determined by means of quantitative autoradiography using [3H]8-cyclopentyl-1 ,3-dipropylxanthine as a radioligand. A significant 50% reduction of CA1 adenosine A1 receptors was observed in patients with dementia independent of the specific pathology. These results suggest that loss of hippocampal adenosine A1 receptors in dementia is not specific for Alzheimer type pathology.

Several lines of evidence support an involvement of the anterior cingulate cortex in the pathophysiology of schizophrenia. Immunocytochemical techniques using antibodies against calcium-binding proteins permit a selective demonstration of certain subgroups of cortical GABAergic interneurons. The anterior cingulate cortex from the brains of schizophrenic patients and control subjects was studied with an antibody against parvalbumin. The immunoreactive structures were assessed qualitatively and quantitatively. Parvalbumin immunoreactivity was detected in a subpopulation of GABAergic local circuit neurons, in axonal structures (including axon cartridges) and in diffuse, band-like neuropil material. Schizophrenic anterior cingulate cortex was found to contain the same interneuron types as controls, but displayed a significant increase of parvalbumin-immunoreactive neuronal soma profiles in layers Va and Vb, whereas the total neuronal density determined in Nissl preparations showed no difference in the two groups. A higher density of parvalbumin-positive local circuit neurons may indicate an increased inhibition of projection neurons, thus altering the neuronal output pattern of the anterior cingulate cortex in schizophrenia.

The prefrontal cortices of healthy control subjects and schizophrenic patients were examined with an antibody mixture against non-phosphorylated neurofilaments (SMI 311). SMI 311 immunoreactivity was observed in numerous pyramidal neurons of layers II to VI and in Cajal-Retzius cells (CRC) of layer I. On the basis of their Golgi-like immunostaining, CRC could be classified into three morphologically heterogeneous groups, which showed different distributions in the two proband groups. The overall density of CRC in layer I did not differ significantly between controls and schizophrenics. However, CRC were more numerous in the lower third of layer I in schizophrenics and in the upper and middle third of layer I in controls. CRC play a key role in neuronal migration, thus, our results support the neurodevelopmental hypotheses of schizophrenic pathophysiology.

The calcium-binding protein parvalbumin (PV) is a marker for a certain subset of GABAergic cortical interneurons. In the present study, indirect immunocytochemistry with an antibody against PV was performed on serial sections of human anterior cingulate cortex (Brodmann's area 24), an important relay centre of the limbic system. PV-positive structures are distributed in a layer- and cell type-specific manner. Based on morphological features and laminar distribution pattern, PV-immunoreactive interneurons are subdivided into eight different classes. PV immunoreactivity within the neuropil comprises dendritic and axonal processes. Area 24 contains two densely immunolabelled neuropil bands in layers III and Vb. Axon cartridges are preferably located in layers V and VI. The results provide a "PV immunoarchitecture' as a basis for further studies of PV immunoreactivity under pathological conditions. PV is assumed to play a role in maintaining calcium homeostasis in nerve cells, and to modulate neuronal excitability and resistance to biochemical damage. On the other hand, PV immunoreactivity has recently been shown to undergo characteristic changes during different stages of brain maturation. Therefore, examination of PV-positive structures will provide new insights into cortical circuitry in neurodegenerative as well as neurodevelopmental disorders.