Mutations affecting inhibitory transmission are also linked to many of our most devastating neurodevelopmental disorders, including autism spectrum disorders (ASD), epilepsy, neonatal hyperekplexia, and intellectual disability (formally mental retardation). Yet in contrast with the excitatory synapse, the symmetric (inhibitory) postsynaptic complex does not have a morphological landmark and its purification using classical strategies is intractable. Thus, the biochemical nature of the symmetric synapse has largely eluded neuroscientists, and remains to this day a relative black box. This basic lack of fundamental knowledge concerning the signaling apparatus of the symmetric synapse poses a critical barrier to understanding how symmetric synapses develop, are modified by activity, or are affected by neurodevelopmental disorders. This proposal will utilize a highly innovative approach to unveil the symmetric synaptic complex, revealing the internal machinery that governs inhibitory synapse development and function.
This research is relevant to the mission of NIH because it seeks to develop new proteomic tools and approaches to discover the protein components of neuronal synapses and quantify how they are altered downstream of genetic mutations associated with neurodevelopmental disorders. Thus, important advances in understanding the etiology of neuropsychiatric conditions, such as autism spectrum disorders can be anticipated. It is also expected that knowledge gained in these studies will shed light on basic mechanisms that govern signaling events within symmetric (inhibitory) synapses, something that is poorly understood, yet critical for unraveling mechanisms that regulate neuronal connectivity.
| Uezu, Akiyoshi; Kanak, Daniel J; Bradshaw, Tyler W A et al. (2016) Identification of an elaborate complex mediating postsynaptic inhibition. Science 353:1123-9 |
