Project: Identification of potential pathogenetic role of a copy number increase of the glycine decarboxylase gene in psychotic disorders.
Structural variants like copy number variations (CNV), i.e., genomic deletions and duplications, have been discovered as rare mutations with sometimes large effect sizes in psychotic disorders. In a family affected by schizoaffective disorder and bipolar disorder with psychotic features, a small supernumerary marker chromosome containing genomic material from the 9p24.1 region was identified, that segregates with disease (J. TCW et al., Stem Cell Reports 2017;8:519-528; C.M. Grochowski et al., Human Mutation 2018;39:939-946). This results in a “duplication” (i.e., 3 copies instead of 2 copies) of some genes in this genomic region and a “triplication” (i.e., 4 copies instead of 2 copies) of the GLDC gene encoding glycine decarboxylase. Glycine decarboxylase degrade glycine, which is a co-agonist at the NMDA receptor. NMDA receptor hypofunction has been postulated to be a major pathophysiological factor in schizophrenia. Our working hypothesis is that the increased GLDC copy number results in increased amounts of the enzyme glycine decarboxylase, which then results in reduced glycine levels in astrocytes, from which it is known to be released by afferent innervation via AMPA receptors. This would then result in decreased availability of glycine at neuronal NMDA receptors and thus NMDA receptor hypofunction.
Using chromosome engineering (gene targeting followed by trans-chromosomal recombination), we have developed mice with 3 or 4 copies of the 9p24.1 genes, which demonstrate phenotypes consistent with neurodevelopmental disorders such as schizophrenia. We are also developing mice with increased copy numbers of only the Gldc gene and of the other 9p24.1 genes except Gldc. With these mice, we want to investigate whether the phenotypes caused by the large CNV mimicking the patients is due to copy number increase of Gldc or due to copy number increase of the other 9p24.1 genes. We want to study how these structural mutations affect biochemical risk pathways and behavior, and in collaboration with Dr. Vadim Bolshakov, an electrophysiologist at McLean Hospital and Harvard Medical School, how these mutations affect synaptic transmission and changes in intrinsic excitability of neurons.