Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci 8: 1586-1594

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: 16.1). 12/2005; 8(11):1586-94. DOI: 10.1038/nn1562
Source: PubMed


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
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    • "Immobility episode is defined as a complete lack of movement besides respiration for at least 1.5 s. Protocol was adapted from Paterlini et al. (2005). Conditioning was carried out in a chamber with a stainless steel grid floor in a sound attenuation box. "
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    ABSTRACT: Disrupted in schizophrenia-1 (DISC1) gene is associated with several neuropsychiatric disorders as it is disrupted by a balanced translocation involving chromosomes 1 and 11 in a large Scottish pedigree with high prevalence of schizophrenia, bipolar disorder and major depression. Since its identification, several mouse models with DISC1 genetic modifications have been generated using different approaches. Interestingly, a natural deletion of 25bp in the 129 mouse strain alters the DISC1 gene reading frame leading to a premature stop codon very close to the gene breakpoint in the mutant allele of the Scottish family. In the present study we confirmed that the 129DISC1(Del) mutation results in reduced level of full length DISC1 in hippocampus of heterozygous mice and we have characterized the behavioral consequences of heterozygous 129DISC1(Del) mutation in a mixed B6129 genetic background. We found alterations in spontaneous locomotor activity (hyperactivity in males and hypoactivity in females), deficits in pre-pulse inhibition (PPI) and also increased despair behavior in heterozygous 129DISC1(Del) mice, thus reproducing typical behaviors associated to psychiatric disorders. Since this mouse strain is widely and commercially available, we propose it as an amenable tool to study DISC1-related biochemical alterations and psychiatric behaviors.
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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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    ABSTRACT: 25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia. We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia. 25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p = 0.044, 95% CI: 1.02–4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p = 0.035, 95% CI: 1.08–8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk. This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population.
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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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