A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel negative regulator of excitatory synaptic activity in the hippocampus

The biological significance of a small supernumerary marker chromosome generating a 9p24.1 duplication/triplication including a triplication of the GLDC gene encoding glycine decarboxylase in two patients with psychosis is unclear. Performing functional genomic fine-mapping using a series of copy number variant mouse models, we identify that additional copies of Gldc reduce extracellular glycine levels as determined by optical FRET in dentate gyrus (DG) but not in CA1, suppressed long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduced the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displayed prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference deficits. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, demonstrating that GLDC negatively regulates excitatory neurotransmission, supporting the view that extra copies of GLDC in the genome may contribute significantly to the development of neuropsychiatric disorders. bulk RNAseq based transcriptomic analyses of two tissues (hippocampus (HPC) and prefrontal cortex (mPFC)) from 9p24.1 deletion, duplication, and triplication as well as control mouse models