Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia

Vawter, Marquis P.; Thatcher, Linn N.; Usen, Nsima; Hyde, T M; Kleinman, Joel E.; Freed, William J.

doi:10.1038/sj.mp.4001158

Cited by 174 publications

(110 citation statements)

References 39 publications

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“…In rat cortex, previous studies have shown that synaptophysin and PSD-95 levels do not exhibit significant decreases with PMI less than 72 hours (Halim et al 2003;Hilbig et al 2004;Siew et al 2004). In human cortex, synaptophysin levels appear to be fairly robust over PMIs of less than 84 hours (but see Vawter et al 2002) (Honer et al 1992Vawter et al 2002). These findings are consistent with our study of the postmortem stability of synaptophysin in rat cortex over 24 hours.…”

Section: Discussionsupporting

confidence: 82%

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

Glantz¹,

Gilmore²,

Hamer³

et al. 2007

Neuroscience

232

162

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Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density-95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1 to 25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence. Keywordsadolescence; development; human; synapses; pruning; synaptogenesisThe human brain has the most protracted period of development of any species, with neurodevelopment continuing well into early adulthood. Imaging studies have shown that in the human, the overall volume of the brain increases during childhood and adolescence (Giedd Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 November 9. Sowell et al. 2002;Gilmore et al. 2007). Specifically, the cortical gray matter volume, particularly the f...

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Section: Discussionsupporting

confidence: 82%

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

Glantz¹,

Gilmore²,

Hamer³

et al. 2007

Neuroscience

232

162

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“…35 A recent study showed both total and individual synapsins to be reduced in the hippocampus of patients with schizophrenia and bipolar disorder, as well as victims of suicide 36 while SYN2 was here observed to be elevated in depressed suicides (area 45). Lastly, multiple probe sets for QKI identified a common pattern of downregulated expression in depressed suicides across all four brain regions studied.…”

Section: Discussionmentioning

confidence: 45%

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

et al. 2007

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The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides = 16, nondepressed suicides = 8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/ oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

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“…Release of glutamate from nerve endings was markedly decreased in the synapsin I mutant mice (Li et al, 1995). The total synapsin (Ia, IIa, and IIIa) protein was reduced in the hippocampus of patients with bipolar disorder, another type of depression besides major depression, implying that altered or reduced synaptic function in the hippocampus may be involved in this disorder (Vawter et al, 2002). In our study, we found that the density of synapsin I immunoreactive synaptic buttons increased significantly in the CA3 subfield after 21 days CUMS.…”

Section: Discussionmentioning

confidence: 97%

“…Chronic treatment with tranylcypromine, but not desipramine or fluoxetine, decreases synapsin I mRNA expression in rat hippocampal DG, CA3, and CA1 (Rapp et al, 2004), and imipramine or fluvoxamine decreases synapsin I immunoreactivity in rat hippocampus (Iwata et al, 2006). Another study showed that injecting rats with lithium for 30 days produces no changes in total synapsin in the hippocampus (Vawter et al, 2002). The effects of mifepristone on the mRNA level of synapsin I are not quite the same as tranylcypromine.…”

Section: Discussionmentioning

confidence: 98%

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

Han

Wang

et al. 2007

Neuropsychopharmacol

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Clinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of depression. The molecular mechanisms of mifepristone involved in the treatment of depression are not fully understood. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAA) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, that is, it increases in dentate gyrus (DG)/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for 1 week. The result suggests that the molecular mechanism underlying the treatment of depression with mifepristone is associated with the rapid repair of the synaptic alteration.

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Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia

Cited by 174 publications

References 39 publications

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

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