High-dose antipsychotic medication

Synapses formed between mossy fibers, the axons of hippocampal dentate granular cells, and the dendrites of CA3 pyramidal neurons are important links within the trisynaptic circuitry. Abnormalities in this circuitry are associated with the failure of schizophrenics to integrate affective experience with higher cognitive function, and with disturbances in memory and spatial learning processes. The abnormalities include reduced size and altered dendritic arborization of CA3 pyramidal neurons. In addition, decreased expression and binding activity of glutamate receptors have been reported, predominantly in the CA3 region of the hippocampus. These findings suggest that there are disturbed neuronal processes and connections in the hippocampus of schizophrenics. An electron microscope morphometric study of synaptic contacts between mossy fiber axon terminals (MFT) and branched dendritic spines of pyramidal neurons in stratum lucidum of the CA3 region of the hippocampus was performed in 10 normal controls and 9 age-matched chronic schizophrenics (postmortem delay 3-9 h). Schizophrenic cases with predominantly positive symptoms had a significantly reduced volume fraction of spines (-35%, P < 0.05), total number of invaginated spines (-47%, P < 0.01), and number of spines forming synapses (-32%, P < 0.05) per MFT compared with the control group. No effects of postmortem delay, age, duration of disease, or neuroleptic exposure were found. These data may reflect decreased efficacy of mossy fiber synapses in the CA3 hippocampal region in schizophrenics with predominantly positive symptoms. These data are in line with the neurodevelopmental hypothesis of schizophrenia.

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Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: A postmortem morphometric study

Kolomeets

Orlovskaya

Rachmanova

et al. 2005

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131

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Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia

Kolomeets

Orlovskaya

2007

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The CA3 region of the hippocampus is unique in its connectivity, its role in cognitive maintenance, and its great vulnerability in schizophrenia. The down regulation of the expression and binding activity of glutamate receptors was revealed in the CA3 hippocampal region and may be attributed to cognitive disturbances in schizophrenia. Our previous study demonstrated that only schizophrenics with predominantly positive (but not predominantly negative) symptoms had smaller-sized branched spines (thorny excrescences) of CA3 pyramidal neurons and fewer synaptic contacts formed by dentate mossy fiber terminals (MFT-synapses). In the present study, we used an unbiased stereological physical dissector method to verify whether the numerical density of MFT-synapses is altered in schizophrenia. A morphometric study was performed in 10 normal controls and eight age-matched cases with chronic schizophrenia, including five cases with predominantly positive and three with predominantly negative symptoms. Schizophrenic cases had a significantly reduced numerical density of MFT-synapses (-25%, P < 0.01) compared with the control group. The decrease was similar in schizophrenic subgroups with predominantly positive and predominantly negative symptoms. No effects of postmortem delay, age, duration of disease, and neuroleptic exposure were found. Taken together with our previous results, the data suggest that the decrease of numerical density of MFT-synapses may be the result of different mechanisms in schizophrenics with predominantly positive and predominantly negative symptoms.

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Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia

Kolomeets¹,

Uranova

2018

Eur Arch Psychiatry Clin Neurosci

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Neuroimaging and post-mortem studies have implicated altered myelin integrity and oligodendrocyte abnormalities in the dysfunction of neuronal network in schizophrenia, including the prefrontal cortex, Brodmann area (BA) 10. Pyramidal neurons in layer 5 of BA10 are the important link of reciprocal frontal cortical-basal ganglia-thalamic circuits altered in schizophrenia. Previously, we found ultrastructural dystrophic and degenerative alterations of oligodendrocytes in layer 5 of BA10 in schizophrenia. The aim of the study was to estimate the numerical density (Nv) of oligodendrocytes in layer 5 of BA10 in schizophrenia as compared to normal controls. 17 chronic schizophrenia subjects and 22 healthy matched controls were studied in Nissl-stained sections using optical disector method. Group differences were analyzed using ANCOVA followed by post hoc Duncan's test. The Nv of oligodendrocytes was significantly lower (- 32%, p < 0.001) in the schizophrenia group as compared to the control group. Young controls (age < 50 years old) showed significantly higher Nv of oligodendrocytes as compared to elderly controls (age > 50 years old). Young and elderly schizophrenia subgroups did not differ significantly. Both control subgroups have significantly higher Nv of oligodendrocytes as compared to the schizophrenia subgroups. Decreased Nv of oligodendrocytes found in layer 5 of BA10 may be the result of dystrophic and destructive alterations and/or disrupted development of oligodendrocytes in schizophrenia.

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High-dose antipsychotic medication

Cited by 18 publications

References 15 publications

Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: A postmortem morphometric study

Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: A postmortem morphometric study

Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia

Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia

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