Uncovering the Role of GIT Proteins in Encoding Acoustic Information.
Final Report Abstract
The perception of acoustic information is based on the transformation of sound waves into temporal precise action potentials between nerve cells. The ability to localize sound sources is crucial for detecting objects and understanding speech in noise. Since the location of a sound source is not represented on the sensory epithelium, the brain must recompute it in real time. This computation requires the highest temporal precision in the mammalian nervous system. Nerve cells in the brain communicate with each other via chemical synapses which rely on the release of neurotransmitter stored in synaptic vesicles in the presynaptic terminal. The temporal dynamics of neurotransmitter release therefore is essential to reliable and temporal precise neuronal communication. To understand how temporal precise signal transmission is achieved and how it is impacted in disease, it is crucial to understand the molecular mechanisms underpinning synaptic vesicle release. A critical synapse in binaural hearing is the calyx of Held – MNTB synapse located in the auditory brainstem which shows extraordinary temporal precision. Recent studies suggest that presynaptic actin impacts synaptic transmission. A key regulator of actin dynamics is the G- protein-coupled receptor kinase interacting (GIT) protein which has been identified to regulate synaptic strength but its role in establishing temporal precise neuronal communication remains elusive. Using a combination of molecular and cellular methods I found that loss of presynaptic GIT proteins increases synaptic vesicle release probability, slows down vesicle replenishment but has little impact on postsynaptic action potentials at near-physiological conditions. Building on those findings, I used viral vectors to ablate presynaptic Rac1 proteins, another regulator of actin dynamics. Loss of Rac1 yielded similar results to loss of GIT with increased synaptic vesicle release probability. However, the replenishment of synaptic vesicles was facilitated after Rac1 ablation. These results suggest that both GIT and Rac1 proteins regulate synaptic strength in the presynaptic terminal but have opposing effects on the replenishment of synaptic vesicles. Future studies will be performed to dissect the molecular mechanisms of these interactions and their role in auditory signal transmission in health and disease.
Publications
- (2019) Presynaptic Mitochondria Volume and Abundance Increase during Development of a High-Fidelity Synapse. J Neurosci 39:7994–8012
Thomas CI, Keine C, Okayama S, Satterfield R, Musgrove M, Guerrero- Given D, Kamasawa N, Young SM
(See online at https://doi.org/10.1523/JNEUROSCI.0363-19.2019)
