1. Molecular mechanisms of synaptic plasticity underlying learning and memory
A neuron communicates with neighboring neurons by releasing neurotransmitters at specialized contact sites, called synapses, and such synaptic transmission plays a major role in delivering information from one neuron to another and also in integrating signals at a neuronal network level. Interestingly, the efficiency of synaptic transmission constantly changes depending on the history of neuronal activation, and in this sense, the connection strength between neurons is considered "plastic". This phenomenon is known as synaptic plasticity, which is widely accepted as a cellular basis of learning and memory formation in the brain.
Synapse is an extremely small cellular compartment, but is heavily loaded with a number of different proteins. A myriad of synaptic proteins must work in a cooperative manner to maintain brain functions, and a mutation or single-nucleotide polymorphism in the genes encoding synaptic proteins can lead to brain disorders. Genome-wide association studies (GWAS) identified numerous risk genes associated with neuropsychiatric disorders, but elucidating how such risk genes contribute to cognitive deficits requires further investigation. Using electrophysiology, calcium imaging and quantitative proteomics, our research group aims to understand how the risk genes associated with neuropsychiatric disorders modulate synaptic plasticity and animal behaviors at the molecular level.
2. Association of aberrant O-GlcNAc modification with neuropsychiatric disorders
O-GlcNAcylation (covalent attachment of a single sugar group to a protein)
is highly dynamic and reversible post-translational modification.
Post-translational modifications (PTMs) of a protein diversify and fine-tune protein functions, thereby contributing to increasing proteome complexity. Along with phosphorylation, another highly abundant PTM is the attachment of a single sugar moiety to serine and threonine residues of a protein, known as O-GlcNAcylation. Given the fact that both phosphorylation and O-GlcNAcylation target serine and threonine, two PTMs can interact and/or compete with each other, and thus O-GlcNAcylation is expected to play a modulatory role similarly to phosphorylation. However, unlike phosphorylation (having a set of specific kinases and phosphatases for each substrate), O-GlcNAcylation is entirely mediated by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), regardless of substrates. Interestingly, both OGT and OGA are highly expressed in the brain (second highest expression in the body after pancreas), and their expression is particularly enriched in the hippocampus.
The identification of proteins undergoing O-GlcNAc modification has been difficult due to the labile nature of the O-GlcNAc moiety, but a recent advance in the proteomic technique enabled the discovery of O-GlcNAcylated proteins in an efficient manner. Notably, the list of O-GlcNAcylated proteins includes a large number of neuron-specific and synaptic proteins, including ion channels and scaffolding proteins of synapses. Despite its prevalence in the brain, however, the functional significance of O-GlcNAcylation in regulating neuronal functions remains unclear at the molecular level. By combining pharmacological and genetic approaches, our research group aims to understand the molecular mechanisms by which O-GlcNAcylation of synaptic proteins modulates neuronal functions, ranging from synaptic transmission to animal behaviors.
Considering that glucose provides a donor molecule for O-GlcNAcylation when metabolized via the hexosamine biosynthetic pathway, pathological conditions with altered blood glucose levels, such as diabetes and obesity, likely suffer from abnormal O-GlcNAcylation levels. Interestingly, both human patients and mouse models of diabetes exhibit the increased risk for cognitive deficits, and also, type 2 diabetes is associated with the increased risk of developing Alzheimer's disease (referred as type 3 diabetes). In this regard, it is critical to understand a mechanistic link between dysregulated O-GlcNAcylation levels and hippocampal dysfunction, which may also reveal a novel correlation between metabolic abnormalities and psychiatric disorders.
