Amisyn at the crossing of modulated neurotransmission and brain pathologies

The human brain is astonishing: it is the source of our thoughts, actions, memories, perceptions and emotions. It confers on us the abilities that make us human, while simultaneously making each of us unique. Through deepened knowledge and understanding of how human brain works, we will comprehend ourselves better and treat brain diseases more incisively. Over recent years, neuroscience has advanced to the level that we can envision spanning molecules, cells and neuronal circuits in action. In particular, there is an emerging view that subtle aspects of presynaptic dysfunction are implicated in an increasing number of brain disorders such as neurological and neurodegenerative diseases.

We are particularly interested in exocytosis, a process of vital importance for neuronal cells that is controlled by a set of both positive and negative regulators. While promotors of exocytosis are well studied, negative regulators are poorly understood. We discovered that a small SNARE protein amisyn (STXBP6) acts as a vertebrate-specific competitor of synaptobrevin-2, a key player in exocytosis. Amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane by binding to phospholipid PI(4,5)P2. Both the pleckstrin homology and SNARE domains are needed to inhibit exocytosis. Of note, amisyn is poorly studied despite several studies have emphasized its importance for exocytosis and reported the occurrence of amisyn mutations in autism, diabetes and cancer.

This PhD project aims to study mechanisms of exocytosis with a focus on amisyn. The candidate will study how lack or impaired function of amisyn modulates exocytosis, synaptic transmission and behavior. We have generated a mouse model without amisyn to be employed for these studies. In addition, our collaborative team has expertise in a wide variety of interdisciplinary techniques to support and facilitate the proposed PhD project, such as biochemical, (electro)physiologal and life confocal microscopy techniques.