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Francesco Papaleo COMT, dysbindin and their interaction: implications for schizophrenia.

Abstract :

The etiology of schizophrenia is complex and largely unknown, with both genetic and environmental contributing factors. Genetic association studies have indicated several potential schizophrenia-susceptibility genes (such as COMT, Dysbindin, DISC1, KCNH2, Neuregulin etc.). Schizophrenia is most likely related to the combination of malfunction of multiple genes, rather than mutation of only a single gene. Using COMT transgenic and knockout mice, dysbindin knockout mice, and COMT*dysbindin double knockout mice, we investigated the implication of COMT and dysbindin gene products, as well as their interaction, in the physiopathology of schizofrenia.
Catechol-O-methyltransferase (COMT) methylates catechol structures, including dopamine, norepinephrine, epinephrine, caffeine, and catechol estrogens. In humans and rodents, COMT plays an important role in the catabolism of cortical dopamine, but not cortical norepinephrine. Dysbindin is encoded by the dystrobrevin-binding protein 1 gene, which is expressed in human and mouse brain neurons. Dysbindin is located in synaptic sites and has been implicated in the regulation of exocytosis and vesicle biogenesis in endocrine cells and neurons.
It has been shown that decreased COMT increase cortical dopamine and decreased dysbindin increases D2 receptor signaling. Thus, based on these evidences, we predicted synergistic effects of reduced COMT and dysbindin expression, which might have result in excessive cortical dopamine signaling.
We found that both single mutation of COMT or dysbindin affect cognitive and stress reactivity measures. However, only genetic modifications reducing both COMT and dysbindin activity produced working memory deficits, hyperactivity, amphetamine supersensitivity and abnormal response to acoustic stimuli. Noteworthy, the latter parameters all reflect rodent correlates of schizophrenia-like core clinical symptoms. These findings demonstrate epistatic interactions between two putative schizophrenia-susceptibility genes, and unravel interesting genetic mechanisms in the etiology of this devastating mental illness.


Selected publications

Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice.Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR, Chen J.
J Neurosci. 2008 Aug 27;28(35):8709-23.

Disruption of the CRF(2) receptor pathway decreases the somatic expression of opiate withdrawal.Papaleo F, Ghozland S, Ingallinesi M, Roberts AJ, Koob GF, Contarino A.
Neuropsychopharmacology. 2008 Nov;33(12):2878-87. Epub 2008 Feb 20.   
Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal.Papaleo F, Kitchener P, Contarino A.
Neuron. 2007 Feb 15;53(4):577-89.