Our studies of mice with COMT genetic variations are used to test hypotheses about extracellular and intracellular mechanisms influenced by dopamine and related to schizophrenia. Our studies have resulted in proposed neural and molecular mechanisms accounting for the diverse pattern of clinical associations that have been examined with COMT. These studies stress how critical epistasis and biologic context are in uncovering and elucidating the complexity of the biologic mechanisms. Due to the complexity of human behavior and the complex set of interacting genetic variants within the COMT gene, the effect of COMT variation is questionable and associations are notably weak at the clinical level. Mutant mice with targeted mutations of COMT are unique tools to elucidate the role of COMT in cognitive function, emotional arousal, and the neurobiological basis for behavioral associations in humans. Genetically altered mice provide a level of molecular specificity that is not possible to obtain in human studies. Mouse models allow us to explore interactions of functional sites in a gene on different genetic backgrounds. We have genetically altered mice lacking functional COMT and a new transgenic (tg) mouse over-expressing the human COMT val and compared them to normal wild-type COMT leucine mice. This approach allows us to contrast life-long effects of genetic variation resulting in relatively low and relatively high COMT activity, respectively. Our research has previously reported that COMT val158met polymorphism alters COMT enzyme activity and is a predictor of the adhesion and migratory responses of B lymphoblast to NRG1. Along with COMT, NRG1-ErbB signaling plays a role in the pathogenesis of schizophrenia. B lymphoblasts express a functional ErbB signaling pathway and NRG1 promotes the adhesion and migration in the B lymphoblast cell model. In Sei (PloS One, 2010) we designed experiments to study AKT1 activation in NRG1-stimulated B lymphoblasts cell model system and examined the possible existence of a functional interaction between COMT and AKT1. We inserted a COMT val construct into SH-SY5Y cells (neuroblastoma cell line) and observed an increase in COMT activity and decreased levels of phosphatidylserine (PS), NRG1-induced AKT1 activation and migration. An analysis of NRG1-induced activation showed reduced phosphorylation in COMT val individuals compared with those carrying the met allele. The data suggest that AKT1 function is influenced by COMT enzyme activity through competition with synthesis of PS, which is a factor that attracts domain of AKT1 to the cell membrane, through S-adenosylmethione (SAM), which regulates AKT1-dependent cellular responses to NRG1-mediated signaling. The effects were reversed with administration of SAM which indicated that AKT1 function is indeed influenced by COMT enzyme activity through competition with PS synthesis for SAM, which regulates AKT1-dependent cellular responses to NRG1-mediated signaling. In this study we show there is a significant interaction of a functional coding polymorphism in AKT1 (rs1130233) and COMT val108/158met genotype on AKT1 activation. We concluded there are genetic and functional interactions between COMT and AKT1 that may provide novel insight into the pathogenesis of schizophrenia. The Transgenic Lab will continue to investigate COMT, Dysbindin, BDNF (Brain-Derived Neurotrophic Factor), ARC (Activity-Regulated Cytoskeleton-associated protein), NRG1 (Neuregulin-1), AKT1 (a serine/threonine protein kinase), KCNH2 (potassium voltage-gated channel) and gene-gene interactions involving COMT to mimic aspects of human behaviors and establish the biologic validation of these associations. Our COMT mouse model reifies that a common genetic factor can be involved in diverse clinical disorders, characterized by abnormal cognitive processing and stress reactivity, and represents a promising new animal model for testing cognitive as well as stress related therapies. While the human behavioral data remains controversial, interpretation of the data in mice is relatively straightforward, and establishes a critical role for the COMT gene. We have demonstrated in our COMT mice all of the major behavioral and pharmacological associations that have been reported in humans. In collaboration with other labs in CBDB/GCAP, we discovered a novel KCNH2-3.1 isoform. The potassium channel was over-expressed in schizophrenia patients, and is being studied as a potential drug target for the treatment of psychosis and cognitive dysfunction of schizophrenia. To date, we have found that haloperidol can block the novel KCNH2-3.1 isoform channel. We developed small hairpin RNA (shRNA) molecules against the novel KCNH2-3.1 isoform and demonstrated that the anti-KCNH2-3.1 isoform shRNA can inhibit the KCNH2-3.1 isoform specifically, but not wild-type KCNH2. We have been collaborating with the genomic chemical center at the National Human Genome Research Institute (NHGRI) to screen chemical libraries for compounds that can inhibit the KCNH2-3.1 isoform. Novel KCNH2-3.1 inhibitors could be a new class of antipsychotic drugs for the treatment of schizophrenia.
| Carr, Gregory V; Jenkins, Kimberly A; Weinberger, Daniel R et al. (2013) Loss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior. Behav Brain Res 241:173-84 |
| Papaleo, F; Yang, F; Garcia, S et al. (2012) Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 17:85-98 |
| Papaleo, Francesco; Weinberger, Daniel R (2011) Dysbindin and Schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry 69:2-4 |
| Papaleo, Francesco; Crawley, Jacqueline N; Song, Jian et al. (2008) Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 28:8709-23 |
| Pezawas, L; Meyer-Lindenberg, A; Goldman, A L et al. (2008) Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 13:709-16 |
