Aberrant glycosylation in schizophrenia: a review of 25 years of post-mortem brain studies

Abstract

Glycosylation, the enzymatic attachment of carbohydrates to proteins and lipids, regulates nearly all cellular processes and is critical in the development and function of the nervous system. Axon pathfinding, neurite outgrowth, synaptogenesis, neurotransmission, and many other neuronal processes are regulated by glycans. Over the past 25 years, studies analyzing post-mortem brain samples have found evidence of aberrant glycosylation in individuals with schizophrenia. Proteins involved in both excitatory and inhibitory neurotransmission display altered glycans in the disease state, including AMPA and kainate receptor subunits, glutamate transporters EAAT1 and EAAT2, and the GABA_A receptor. Polysialylated NCAM (PSA-NCAM) and perineuronal nets, highly glycosylated molecules critical for axonal migration and synaptic stabilization, are both downregulated in multiple brain regions of individuals with schizophrenia. In addition, enzymes spanning several pathways of glycan synthesis show differential expression in brains of individuals with schizophrenia. These changes may be due to genetic predisposition, environmental perturbations, medication use, or a combination of these factors. However, the recent association of several enzymes of glycosylation with schizophrenia by genome-wide association studies underscores the importance of glycosylation in this disease. Understanding how glycosylation is dysregulated in the brain will further our understanding of how this pathway contributes to the development and pathophysiology of schizophrenia.

Figure 1.. Glycoproteins and glycoenzymes altered in schizophrenia through gene expression and post-mortem studies.

Numerous studies primarily in post-mortem brain samples have identified altered glycosylation of multiple neuronal proteins, as well as changes in the expression of glycosyltransferase enzymes. Presynaptic neuron is shown in green, postsynaptic neuron in blue, astrocyte in red. Glycans included for illustrative purposes, with monosaccharides coded according to SNFG guidelines (https://www.ncbi.nlm.nih.gov/glycans/snfg.html). Perineuronal Nets - PNN; Polysialylated Neuronal Cell Adhesion Molecule - PSA-NCAM.