Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice

Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.
Nature Neuroscience (Impact Factor: 14.98). 12/2005; 8(11):1586-94. DOI: 10.1038/nn1562
Source: PubMed

ABSTRACT Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.

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Available from: Marta Paterlini, Jul 28, 2015
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    • "Proline can also modulate glutamatergic neurotransmission , as supported by the specificity of proline active uptake to a subset of glutamatergic terminals, its ability to inhibit glutamate release at high concentrations, and the finding of reduced glutamate uptake in the hyperprolinemic rat brain (Cohen and Nadler, 1997; Phang et al., 2001; Ferreira et al., 2012). While studies of elevated proline in humans (22q11DS patients (Karayiorgou and Gogos, 2004), hyperprolinemia types I and II (Phang et al., 2001)) and a chronic proline administration model (Shanti et al., 2004), have documented the pathogenic properties of hyperprolinemia, the consequences of elevated proline for CNS neurotransmission have been best demonstrated by work on the hyperprolinemic Prodh null mouse (Gogos et al., 1999; Paterlini et al., 2005), which in the presence of POX deficiency and elevated proline (peripheral and CNS), exhibits a deficit in sensorimotor gating, increased sensitivity to amphetamine, and impairments in declarative memory, coupled with locally decreased CNS glutamate and GABA, increased neurotransmitter release at glutamatergic synapses, and possible activation of dopaminergic signaling. The results of our current study therefore present a mechanism by which vitamin D insufficiency confers risk of schizophrenia ; via reduced PRODH expression, proline elevation, and the concomitant dysregulation of neurotransmission. "
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    Schizophrenia Research 06/2014; 156(1). DOI:10.1016/j.schres.2014.03.017 · 4.43 Impact Factor
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    • "A deficit in associative learning was detected in a mouse model of PRODH deficiency that mimics the status in 22q11.2DS (Paterlini et al., 2005). "
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    Journal of Psychiatric Research 05/2014; 56. DOI:10.1016/j.jpsychires.2014.04.019 · 4.09 Impact Factor
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    • "e l s e v i e r. c o m / l o c a t e / p s y c h i r e s PRODH enzyme, a mitochondrial proline dehydrogenase that catalyzes the first step in proline catabolism. PRODH hemizygous deletion is thought to alter the glutamatergic and dopaminergic transmission (Henzi et al., 1992; Paterlini et al., 2005). To further investigate the role of COMT and PRODH in the 22q11.2DS "
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    ABSTRACT: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.
    Journal of Psychiatric Research 08/2013; 47(11). DOI:10.1016/j.jpsychires.2013.07.004 · 4.09 Impact Factor
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