Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers

Mexal, Sharon; Frank, Marcos G.; Berger, Ralph; Adams, Catherine E.; Ross, Randal G.; Freedman, Robert; Leonard, Sherry

doi:10.1016/j.molbrainres.2005.06.006

Cited by 88 publications

(111 citation statements)

References 95 publications

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“…Further support for the potential involvement of Egr3 in the pathology of schizophrenia comes from recent studies, which found that the expression of Egr3 was significantly lower in the brains of schizophrenia patients compared to controls (Mexal et al, 2005;Yamada et al, 2007). The fact that the human Egr3 gene resides at the chromosomal location 8p21.3, which linkage analyses have identified as a major schizophrenia locus (Blouin et al, 1998;Kendler et al, 2000;Gurling et al, 2001;Lewis et al, 2003) highlights the potential for dysfunction of Egr3 to contribute to this disorder.…”

Section: Egr3 and Schizophreniamentioning

confidence: 96%

Mice Lacking the Immediate Early Gene Egr3 Respond to the Anti-Aggressive Effects of Clozapine Yet are Relatively Resistant to its Sedating Effects

Gallitano

Wozniak

Pehek

et al. 2007

Neuropsychopharmacol

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Immediate early genes (IEGs) of the early growth response gene (Egr) family are activated in the brain in response to stress, social stimuli, and administration of psycho-active medications. However, little is known about the role of these genes in the biological or behavioral response to these stimuli. Here we show that mice lacking the IEG transcription factor Egr3 (Egr3À/À mice) display increased aggression, and a decreased latency to attack, in response to the stressful social stimulus of a foreign intruder. Together with our findings of persistent and intrusive olfactory-mediated social investigation of conspecifics, these results suggest increased impulsivity in Egr3À/À mice. We also show that the aggression of Egr3À/À mice is significantly inhibited with chronic administration of the antipsychotic medication clozapine. Despite their sensitivity to this therapeutic effect of clozapine, Egr3À/À mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls. This indicates that the therapeutic, anti-aggressive action of clozapine is separable from its sedating activity, and that the biological abnormality resulting from loss of Egr3 distinguishes these different mechanisms. Thus Egr3À/À mice may provide an important tool for elucidating the mechanism of action of clozapine, as well as for understanding the biology underlying aggressive behavior. Notably, schizophrenia patients display a similar decreased susceptibility to the side effects of antipsychotic medications compared to non-psychiatric controls, despite the medications producing a therapeutic response. This suggests the possibility that Egr3À/À mice may provide insight into the neurobiological abnormalities underlying schizophrenia.

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Section: Egr3 and Schizophreniamentioning

confidence: 96%

Mice Lacking the Immediate Early Gene Egr3 Respond to the Anti-Aggressive Effects of Clozapine Yet are Relatively Resistant to its Sedating Effects

Gallitano

Wozniak

Pehek

et al. 2007

Neuropsychopharmacol

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“…One method is to develop animal and cellular models that have profiles similar to BPD and SZ gene expression profiles and to show that the pathophysiology involves mitochondrial-related gene expression. The other method is to perform rigorously controlled studies of covariates and gene expression (62,69,(79)(80)(81) which we further comment upon below.…”

Section: Altered Mitochondrial Gene Expression In Psychiatric Disordersmentioning

confidence: 99%

Mitochondrial involvement in psychiatric disorders

et al. 2008

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Recent findings of mitochondrial abnormalities in brains from subjects with neurological disorders have led to a renewed search for mitochondrial abnormalities in psychiatric disorders. A growing body of evidence suggests that there is mitochondrial dysfunction in schizophrenia, bipolar disorder, and major depressive disorder, including evidence from electron microscopy, imaging, gene expression, genotyping, and sequencing studies. Specific evidence of dysfunction such as increased common deletion and decreased gene expression in mitochondria in psychiatric illnesses suggests that direct examination of mitochondrial DNA from postmortem brain cells may provide further details of mitochondrial alterations in psychiatric disorders.

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“…The most significantly changed group of genes were those playing a role in the NMDA-PSD. More importantly, in schizophrenic smokers, 77 genes were differentially regulated by smoking (Mexal et al, 2005). The differential regulation fit specific patterns showing that gene expression was abnormal in schizophrenic non-smokers, compared to control subjects (either up-or down-regulated).…”

Section: Consequences Of Decreased Levels Of Nicotinic Receptors In Smentioning

confidence: 62%

“…If the expression of a specific gene was up-regulated in schizophrenic nonsmokers, in schizophrenic smokers expression was decreased to control levels. If the expression was decreased in schizophrenic non-smokers, compared with controls, it was increased to control expression values in schizophrenic smokers (Mexal et al, 2005). The microarray results were confirmed by real-time quantitative PCR (qRTPCR).…”

Section: Consequences Of Decreased Levels Of Nicotinic Receptors In Smentioning

confidence: 77%

See 1 more Smart Citation

Genetics of Smoking and Schizophrenia

Leonard¹,

Mexal²,

Freedman³

2007

Journal of Dual Diagnosis

111

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Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The α7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an α7* agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.Schizophrenia and smoking are closely connected. The prevalence of tobacco use in schizophrenia is inordinately high. Only 25% of the general population now smokes, but more than 80% of schizophrenics use tobacco products (de Leon and Diaz, 2005;Diwan et al

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Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers

Cited by 88 publications

References 95 publications

Mice Lacking the Immediate Early Gene Egr3 Respond to the Anti-Aggressive Effects of Clozapine Yet are Relatively Resistant to its Sedating Effects

Mice Lacking the Immediate Early Gene Egr3 Respond to the Anti-Aggressive Effects of Clozapine Yet are Relatively Resistant to its Sedating Effects

Mitochondrial involvement in psychiatric disorders

Genetics of Smoking and Schizophrenia

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