Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle. Issue 2 (2nd July 2020)

• Record Type: Journal Article
• Authors: Bonnycastle, Katherine; Davenport, Elizabeth C.; Cousin, Michael A.
• Other Names: Cousin Michael A. guestEditor.; Smillie Karen guestEditor.; Gordon Sarah guestEditor.
• Is Part Of: Journal of neurochemistry. Volume 157:Issue 2(2021)
• Page Start: 179
• Page End: 207
• Publication Date: 2020-07-02
• Subjects: autism -- endocytosis -- epilepsy -- exocytosis -- intellectual disability -- neurotransmission -- vesicle; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15035
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: The activity‐dependent fusion, retrieval and recycling of synaptic vesicles is essential for the maintenance of neurotransmission. Until relatively recently it was believed that most mutations in genes that were essential for this process would be incompatible with life, because of this fundamental role. However, an ever‐expanding number of mutations in this very cohort of genes are being identified in individuals with neurodevelopmental disorders, including autism, intellectual disability and epilepsy. This article will summarize the current state of knowledge linking mutations in presynaptic genes to neurodevelopmental disorders by sequentially covering the various stages of the synaptic vesicle life cycle. It will also discuss how perturbations of specific stages within this recycling process could translate into human disease. Finally, it will also provide perspectives on the potential for future therapy that are targeted to presynaptic function. Abstract : This review article summarizes current knowledge regarding how mutations in synaptic vesicle recycling genes linked in neurodevelopmental disorders impact on brain function. It covers the "normal" function of the gene, how mutations disrupt function and translate into a neurodevelopmental disorder. These mutations cause disruption of almost all aspects of the synaptic vesicle life cycle, suggesting dysfunction at different stages can result in a similar neurodevelopmental outcome. This also suggests that intervention at a specific point of the cycle may have a wider therapeutic benefit than the event directly affected by the mutated gene.