Phenotype of schizophrenia: a review and formulation

Tamminga, Carol A.; Holcomb, Henry H.

doi:10.1038/sj.mp.4001563

Cited by 234 publications

(164 citation statements)

References 154 publications

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“…63,64 Abnormal social interaction, that is, decreased non-aggressive social activity, may be correlated with negative symptoms of the disease. 1,2 Our results indicate that mutant expression of mutant hDISC1 led to impaired spatial spatial memory (the probe trial) without significantly affecting the performance of the mice during the training session. Notably, it was shown that the probe trial reflects spatial learning better than measure of escape latencies during training.…”

Section: Discussionmentioning

confidence: 69%

“…Live mice anesthetized by isoflurane were imaged with a 9.4 T nuclear magnetic resonance scanner (Bruker Biospin, Billerica, MA, USA). Fast-spin echo sequence was used for T 2 Image analysis. The images were processed using Amira (TGS, San Diego, CA, USA).…”

Section: Magnetic Resonance Imaging (Mri)mentioning

confidence: 99%

“…1,2 There are gender differences in age of onset and clinical features. 3,4 Numerous genetic linkage and association studies have identified regions of the genome that may harbor schizophrenia risk genes, but the complex genetics and symptomatology of the disease have impeded efforts to identify clear genetic determinants.…”

Section: Introductionmentioning

confidence: 99%

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Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

et al. 2007

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A strong candidate gene for schizophrenia and major mental disorders, disrupted-inschizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.

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Section: Discussionmentioning

confidence: 69%

Section: Magnetic Resonance Imaging (Mri)mentioning

confidence: 99%

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Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

et al. 2007

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“…42,43 As the circuitry of corticocortical and thalamocortical projections in the PFC by and large relies on glutamate signaling, expression of glutamate receptors and their interacting PSD molecules in this area have been hypothesized to be altered in schizophrenia. In order to complement and expand on previous studies of abnormal expression of transcripts for glutamatergic proteins in schizophrenia, the present work contains an analysis of protein expression of NMDA receptor subunits and their interacting PSD molecules, PSD-95, SAP102, PSD-93 and NF-L in dorsolateral PFC (DLPFC) and anterior cingulate cortex (ACC).…”

Section: Introductionmentioning

confidence: 99%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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“…Despite the introduction of atypical antipsychotics, whose mechanism of action has been attributed to the antagonism of 5-HT2A receptors coupled to weaker antagonism of dopamine D2 receptors, only 10-20% of schizophrenic patients show a good outcome, recovering to pre-illness levels of functioning, while another 15-20% show a poor outcome and are considered treatment-resistant; the middle group exhibits a range of residual cognitive, psychotic, affective and psychosocial symptoms despite medications (Tamminga and Holcomb, 2005).…”

Section: Introductionmentioning

confidence: 99%

The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: A double-blind, placebo-controlled study

Zoccali

Muscatello

Bruno

et al. 2007

Schizophrenia Research

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Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results, the present 24-week double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 200 mg/day of lamotrigine or a placebo. A final sample of fifty-one patients completed the study.The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative, positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.

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Phenotype of schizophrenia: a review and formulation

Cited by 234 publications

References 154 publications

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: A double-blind, placebo-controlled study

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