Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia

Féron, François; Perry, Christopher; Hirning, M.H.; McGrath, John J.; Mackay‐Sim, Alan

doi:10.1016/s0920-9964(99)00055-9

Cited by 109 publications

(80 citation statements)

References 27 publications

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“…These findings indicate that there are fundamental abnormalities, in schizophrenia, in the neural circuitry underlying olfaction. This is consistent with recent invitro data suggesting abnormalities of olfactory receptor neurons in post-mortem (Arnold et al, 2001) and biopsy (Feron et al, 1999;McCurdy et al, 2006) material.…”

Section: Introductionsupporting

confidence: 93%

Olfactory physiological impairment in first-degree relatives of schizophrenia patients

Turetsky

Kohler

Gur

et al. 2008

Schizophrenia Research

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Background-Efforts to characterize genetic vulnerability to schizophrenia are increasingly focused on the identification of endophenotypes -neurobiological abnormalities that are evident in individuals at risk. Behavioral studies have demonstrated olfactory impairments in odor detection and identification in unaffected 1 st -degree relatives of schizophrenia patients, suggesting that abnormalities in this simple sensory system may serve as candidate endophenotypes. It is unclear, however, whether these behavioral abnormalities reflect basic olfactory sensory processing deficits or nonspecific disruptions of attention and cognition.Method-Unirhinal chemosensory olfactory evoked potentials were acquired from 14 unaffected 1 st -degree relatives of schizophrenia patients and 20 healthy individuals with equivalent age and gender distributions, using 3 different concentrations of hydrogen sulfide. Subjects were also assessed behaviorally for ability to detect and identify odors.Results-Family members exhibited left nostril olfactory detection impairments and bilateral olfactory identification abnormalities. They had reduced evoked potential response amplitudes for the initial N1 component in the left nostril. The subsequent P2 evoked potential response was reduced bilaterally. The pattern and magnitude of family member deficits were comparable to those previously observed for schizophrenia patients.Conclusion-1 st -degree relatives of schizophrenia patients exhibit specific neurophysiological impairments in early olfactory sensory processing. The presence of these neurophysiological abnormalities in both schizophrenia patients and their unaffected 1 st -degree relatives suggests that these represent genetically mediated vulnerability markers or endophenotypes of the illness.

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Section: Introductionsupporting

confidence: 93%

Olfactory physiological impairment in first-degree relatives of schizophrenia patients

Turetsky

Kohler

Gur

et al. 2008

Schizophrenia Research

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“…In SZ ONS cells we predicted and found alterations in cell signalling pathways involved in cell proliferation, neurogenesis and cell adhesion (Féron et al, 1999;McCurdy et al, 2006), whereas skin fibroblasts from the same patients did not show these altered pathways. In PD ONS cells we predicted and found convergence on molecular pathways previously associated with this disorder -namely, mitochondrial function, oxidative stress and xenobiotic metabolism (Henchcliffe and Beal, 2008).…”

Section: Introductionmentioning

confidence: 79%

“…The olfactory mucosa, the organ of smell in the nose, is a neural tissue that is accessible in human adults (Féron et al, 1998) and demonstrates disease-dependent alterations in cell biology in Alzheimer's disease, Rett syndrome, fragile X syndrome and SZ (Wolozin et al, 1992a;Abrams et al, 1999;Féron et al, 1999;Arnold et al, 2001;Ronnett et al, 2003;McCurdy et al, 2006). The olfactory sensory neurons are replaced by neurogenesis that continues throughout adult life from stem cells on the basement membrane (Mackay-Sim and Kittel, 1991;Leung et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Disease-specific, neurosphere-derived cells as models for brain disorders

Matigian

Abrahamsen

Sutharsan

et al. 2010

Disease Models &Amp; Mechanisms

181

237

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SUMMARYThere is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.

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“…2008), and in psychiatric and neurodegenerative diseases (Feron et al, 1999;Hahn et al, 2005;Johnson et al, 1994). The distinct characteristics of embryonic OE precursors focus attention not only on molecular markers for adult counterparts, but on locations for a supportive niche, similar to those in other mature regenerating epithelia, including gut, lung and -in lower vertebrates -the retina (Borthwick et al, 2001;Hitchcock et al, 2004;Wong and Wright, 1999).…”

Section: Defining Oe Neural Stem Cells Throughout Lifementioning

confidence: 99%

Proliferative and transcriptional identity of distinct classes of neural precursors in the mammalian olfactory epithelium

et al. 2010

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SUMMARYNeural precursors in the developing olfactory epithelium (OE) give rise to three major neuronal classes -olfactory receptor (ORNs), vomeronasal (VRNs) and gonadotropin releasing hormone (GnRH) neurons. Nevertheless, the molecular and proliferative identities of these precursors are largely unknown. We characterized two precursor classes in the olfactory epithelium (OE) shortly after it becomes a distinct tissue at midgestation in the mouse: slowly dividing self-renewing precursors that express Meis1/2 at high levels, and rapidly dividing neurogenic precursors that express high levels of Sox2 and Ascl1. Precursors expressing high levels of Meis genes primarily reside in the lateral OE, whereas precursors expressing high levels of Sox2 and Ascl1 primarily reside in the medial OE. Fgf8 maintains these expression signatures and proliferative identities. Using electroporation in the wild-type embryonic OE in vitro as well as Fgf8, Sox2 and Ascl1 mutant mice in vivo, we found that Sox2 dose and Meis1 -independent of Pbx co-factors -regulate Ascl1 expression and the transition from lateral to medial precursor state. Thus, we have identified proliferative characteristics and a dose-dependent transcriptional network that define distinct OE precursors: medial precursors that are most probably transit amplifying neurogenic progenitors for ORNs, VRNs and GnRH neurons, and lateral precursors that include multi-potent self-renewing OE neural stem cells.

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Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia

Cited by 109 publications

References 27 publications

Olfactory physiological impairment in first-degree relatives of schizophrenia patients

Olfactory physiological impairment in first-degree relatives of schizophrenia patients

Disease-specific, neurosphere-derived cells as models for brain disorders

Proliferative and transcriptional identity of distinct classes of neural precursors in the mammalian olfactory epithelium

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