Schizophrenia at the Synapse

A patient receives the diagnosis of schizophrenia when two or more of the following symptoms are present: delusions, hallucinations, disorganized speech, abnormal psychomotor behavior, and so-called negative symptoms such as diminished emotional expression or avolition. But because these symptoms present in a highly variable manner in patients, the underlying genetic causes have been challenging to define. Some of these traits have emerged in people who use the drugs ketamine or phencyclidine (PCP), which are glutamate [ N -methyl-d-aspartate (NMDA)] receptor antagonists. Since these observations, there has been an accumulation of evidence implicating glutamatergic dysfunction in schizophrenia. Now, Fromer and colleagues offer insights garnered from their study of de novo mutations in schizophrenic patients. The new study is the largest analysis of de novo mutations in schizophrenia to date. De novo mutations are mutations that are present in patients but not present in the somatic cell lineages of the parents. Here, the authors performed whole-exome sequencing in an analysis of 617 schizophrenia patient– parent trios and compared their results with published whole-exome sequencing data from 731 control subjects. They identified and validated 637 de novo coding or splice mutations in the schizophrenic subjects. In cases for which the parental origin of the mutated allele was resolvable, 79% of de novo mutations were paternally derived. The authors found that schizophrenics do not have substantially elevated numbers of de novo mutations relative to controls; however, loss-of-function (LOF) mutations were more common in patients who exhibited signs of cognitive impairment. Most strikingly, the authors discovered a substantial enrichment, in schizophrenic patients, of nonsynonymous (amino acid–altering) mutations in genes that encode proteins that influence synapse function, including postsynaptic density proteins, the ARC (activity-regulated cytoskeleton-associated protein) complex, and proteins associated with the NMDA receptor. The ARC complex is expressed by glutamatergic neurons in the brain and has a central role in synaptic plasticity. For example, ARC regulates activity-dependent AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)–receptor trafficking at the synapse as well as structural changes in dendritic spines. In the current study, LOF mutations in ARC complex proteins were enriched 17-fold in schizophrenic relative to control subjects, whereas an independent study reported a 19-fold enrichment. Fromer and colleagues also discovered that aberrant proteins encoded by genes with schizophrenia-associated de novo mutations exhibited more protein-protein interactions than expected by chance and that the mutations converge on a network of proteins that influence glutamatergic synapse functions. Further studies will be needed to decipher how different mutations contribute to the various clinical presentations of schizophrenia and to devise treatment strategies that target ARC functions or related pathways. M. Fromer et al ., De novo mutations in schizophrenia implicate synaptic networks. Nature , published online 22 January 2014 (10.1038/nature12929). [[Abstract]][1] [1]: http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature12929.html