Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia

Harrison, Paul J.; Eastwood, Sharon L.

doi:10.1002/hipo.1067

Cited by 203 publications

(75 citation statements)

References 154 publications

(121 reference statements)

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“…Neuropil consists of the lattice of glial cells and their processes, dendrites, and proximal axons surrounding neuron cell bodies. The hypothesis of neuropil reduction in the hippocampus in MDD is supported by other postmortem studies revealing a decrease in dendritic spine density on neurons and diminished arborization of apical dendrites in the subiculum in a small group of mixed subjects with bipolar disorder or depression (Rosoklija et al 2000) and decreased level of synaptic proteins found in CA4 hippocampal region in bipolar depression (Harrison and Eastwood 2001). Thus, the diminished volume of the hippocampus in depression that some studies have found may be critically determined by a loss in neuropil including dendritic branching, dendritic spine complexity, and glial processes.…”

Section: Discussionmentioning

confidence: 62%

Cellular changes in the postmortem hippocampus in major depression

Stockmeier

Mahajan

Konick

et al. 2004

Biological Psychiatry

642

370

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Section: Discussionmentioning

confidence: 62%

Cellular changes in the postmortem hippocampus in major depression

Stockmeier

Mahajan

Konick

et al. 2004

Biological Psychiatry

642

370

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“…A reduction of neuropil entails compromised cell structure and impoverishment of neuronal connectivity so that a loss in functional communication between neurons is presumed to occur. Several studies reported changes in synaptic proteins and their gene expression (Kung et al, 1998;Karson et al, 1999;Glantz and Lewis, 2000;Harrison and Eastwood, 2001;Mirnics et al, 2001). These findings support a diminishment or dysfunction of dendrites, neurites, and synapses in schizophrenia.…”

Section: Introductionmentioning

confidence: 73%

S100B Serum Levels and Long-Term Improvement of Negative Symptoms in Patients with Schizophrenia

Rothermundt

Ponath

Gläser

et al. 2004

Neuropsychopharmacol

109

104

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S100B, a calcium-binding protein produced by astroglial cells, mediates paracrine and autocrine effects on neurons and glial cells. It regulates the balance between proliferation and differentiation in neurons and glial cells by affecting protective and apoptotic mechanisms. Post-mortem studies have demonstrated a deficit in synapses and dendrites in brains of schizophrenics. Recent studies have shown increased S100B levels in medicated acutely psychotic schizophrenic patients as well as unmedicated or drug naive schizophrenics. One study reported a positive correlation between negative symptoms and S100B. S100B serum levels (quantitative immunoassay) and psychopathology (Positive and Negative Syndrome Scale, PANSS) were examined upon study admission and after 12 and 24 weeks of standardized treatment in 98 chronic schizophrenic patients with primarily negative symptoms. Compared to age-and sex-matched healthy controls, the schizophrenic patients showed significantly increased S100B concentrations upon admission and after 12 and 24 weeks of treatment. High PANSS negative scores were correlated with high S100B levels. Regression analysis comparing psychopathology subscales and S100B identified negative symptomatology as the predicting factor for S100B. S100B is not just elevated during acute stages of disease since it remains elevated for at least 6 months following an acute exacerbation. With regard to psychopathology, negative symptomatology appears to be the predicting factor for the absolute S100B concentration. This might indicate that S100B in schizophrenic patients either promotes apoptotic mechanisms by itself or is released from astrocytes as part of an attempt to repair a degenerative or destructive process.

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“…29 In humans, hippocampal abnormalities have been identified as important susceptibility factors for schizophrenia. [30][31][32][33][34] Recently, extensive studies have been focusing on information-processing deficits, as manifested by sensorimotor gating, in schizophrenia and other neuropsychiatric disorders. Nevertheless, how hippocampal abnormalities contribute to information-processing deficits remains to be explicated.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Hf-1b/Sp4, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. Molecular Psychiatry ( Keywords: transcription factor; hippocampus; schizophrenia; mouse model; behavior; Cre recombinase; genetic rescue Sp1, the prototypal member of the Sp family of transcription factors, has been demonstrated to be essential for embryogenesis. 1 The reduction of its expression in heterozygous Sp1 mice causes a decreased expression of its downstream target gene, MeCP2, whose mutation is responsible for Rett syndrome, a human neurodevelopmental disorder. 2 Recently, Sp1 and other glutamine-rich transcription factors have been implicated in the pathogenesis of neurodegenerative diseases. 3,4 Sp4, also known as HF1b, is another member of the Sp1 family of transcription factors. Sp1 and Sp4 proteins have approximately 50% homology in primary structure, which consists of two glutamine-rich transcription activation domains and Cterminal three zinc-finger DNA binding domains. 5 Both proteins recognize the same DNA binding motif with similar affinity, and often functionally substitute for each other in vitro. 6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes. The generated hypomorphic Sp4 allele mice were grossly normal and displayed no increased lethality. Unexpectedly, the mutant mice displayed both vacuolization in the hippocampus and abnormal behavioral phenotypes, particularly with regard to contextual memory and sensorimotor gating deficits. Hence, these studies suggest a new molecular pathway involving the Sp4 gene that functions within the hippocampu...

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Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia

Cited by 203 publications

References 154 publications

Cellular changes in the postmortem hippocampus in major depression

Cellular changes in the postmortem hippocampus in major depression

S100B Serum Levels and Long-Term Improvement of Negative Symptoms in Patients with Schizophrenia

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

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