Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice.
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.
Paterlini
Marta
M
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.
Zakharenko
Stanislav S
SS
Lai
Wen-Sung
WS
Qin
Jie
J
Zhang
Hui
H
Mukai
Jun
J
Westphal
Koen G C
KG
Olivier
Berend
B
Sulzer
David
D
Pavlidis
Paul
P
Siegelbaum
Steven A
SA
Karayiorgou
Maria
M
Gogos
Joseph A
JA
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002892:Chromosomes, Human, Pair 22; D033481:Chromosomes, Mammalian / Q000502:physiology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D010641:Phenotype; D011394:Proline Oxidase / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D015533:Transcriptional Activation
D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D011394:Proline Oxidase