The Effects of Disruption of Synaptic Signaling on Neuronal Networks

Abstract

The brain is an organ that acts as the conductor of an orchestra – it governs all vital body functions and assures that all organs operate in harmony. Moreover, it plays a crucial role in various tasks such as memory formation, sensory processing and movement control. The performance of the brain in these tasks requires spatiotemporal patterns formed by the activity of different parts of the brain. The formation of the spatiotemporal patterns in the brain is facilitated by the connections between neurons, also known as synapses. Therefore, transmission failure in synapses may lead to disruption in these patterns and may impair the proper functioning of the brain. The aim of this dissertation is to explore the outcomes when synaptic transmission is disrupted. First, we investigated the universal effect of synaptic failure in neuronal networks having heterogeneous connectivity. Even though human studies on anesthetics claimed that failure in signal transmission in the brain results in loss of coherence in brain activity, we provided evidence that this may not always be true. On the contrary, synaptic failure may facilitate the emergence of coherent neuronal network activity due to more balanced input levels across the neuronal network. The second part of this dissertation focuses on a specific case which arises from disruption in synaptic signaling in the peripheral auditory system, namely hidden hearing loss (HHL). We built a computational model to simulate two mechanisms that give rise to HHL: 1) loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) and 2) myelin defects at the peripheral SGN axons. We concluded that both mechanisms decrease the cumulative SGN activity, whereas only myelin defects desynchronize it, confirming the experimental observations. Finally, we investigated the effect of SGN myelin defects on sound localization, as patients with HHL were shown to have binaural processing deficits. We provided evidence that the activity of the neurons in the downstream cochlear nucleus circuit that is responsible for sound localization is severely impaired as a result of myelin defects in SGN fibers. This result possibly elucidates the mechanism that gives rise to sound localization deficiencies in HHL patients.