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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    • "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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    • "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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    • "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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