UC Berkeley

Information processing in the brain involves communication between neurons at structures called synapses. Billions of neurons can have trillions of synaptic connections, each with varying properties of communication with nearby neurons. My dissertation research studies neurotransmitter release at synapses of the fruit fly (Drosophila) larval neuromuscular junction (NMJ), the sites of contact between a motor neuron and a muscle fiber. These glutamatergic synapses closely resemble the excitatory synapses of the vertebrate central nervous system. Each fly NMJ consists of an axon of a single neuron which forms hundreds of synapses onto a single postsynaptic cell, so that pre-post molecular cues are expected to be the same. Nevertheless, basal presynaptic strength (the probability that an action potential will evoke transmitter release, Pr) differs greatly (by as much as 100-fold) between synapses. My analysis shows that synapses with differing Pr are distributed randomly so that synapses situated within a micrometer of each other within the same bouton can differ greatly in Pr. Despite a general tendency toward facilitation of synapses with low basal Pr and depression of synapses with high basal Pr, I observe a remarkable diversity in facilitation/depression across synapses with similar basal Pr. The molecular underpinnings and functional relevance of these forms of synapse diversity remain to be elucidated. I find that the combination of diverse basal transmitter release and plasticity between synapses of type Ib axons, and between type Ib and type Is axons, generate broad distributions of weak and strong synapses across firing frequency, a robustness that maintains a stable average output. I examine the role in this process of the presynaptic glutamate-activated inhibitory auto-receptor, the G protein coupled receptor DmGluR. In Chapter 1, I review fundamental concepts of probabilistic synaptic release and propose applications of these models to the Drosophila larval neuromuscular junction. In Chapter 2, I report on input-specific differences between type Ib and Is axons in basal transmission properties using a ground-breaking in vivo imaging and analysis technique, Quantal Synaptic Optical Reconstruction (“QuaSOR”), which makes it possible to measure evoked and spontaneous transmission at hundreds of identified synapses simultaneously. I characterize differences in transmission, plasticity and homeostatic plasticity between two convergent inputs--from Ib and Is motor neurons-- onto the same postsynaptic muscle fiber. In Chapter 3, I formalize an analytical framework to examine the spatiotemporal nature of evoked and spontaneous transmission at low and high frequency of motor neuron action potential firing in relation to the spatial location and the distribution of presynaptic molecules. I characterize a fundamental result from my research demonstrating how the NMJ as a whole exhibits stable levels of neurotransmitter release despite large variance at individual synapses. Next, I examine spatiotemporal patterns of activity and conclude that active zones are not spatially arranged by synaptic strength but rather are distributed across the entirety of the neuromuscular junction in a more random fashion.