Synaptic Transmission: Mechanisms and Modulation

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Neural processing, be it reflexive responses to touching a hot stove or the emotionally charged recollection of a memory upon hearing a sad song, is due to the activity of neural circuits comprised of electrically active neurons that communicate with each other at specialized sites of contact called synapses. The computational capabilities of any circuit arise from the intrinsic electrical properties of the neurons, their pattern of connectivity and the properties of synapses that connect them. Our research program addresses the fundamental processes of neurotransmission, it's modulation and the ways in which synapses determine the computational properties of neural circuits. Neurotransmission is a highly regulated exocytotic process in which transmitter-containing vesicles fuse with the presynaptic membrane to release their contents. The transmitter diffuses a short distance to bind to receptors on the postsynaptic target. The strength of the connection between the neuronal pair depends on the density of receptors on the postsynaptic side and the amount of transmitter that is released from the presynaptic side. Ca2+ ion concentration in the presynaptic terminal controls the number of vesicles that fuse which in turn determines the amount of transmitter released. Our research program uses a variety of "model" synapses chosen for their advantageous physiology and anatomy or because they exhibit distinct release or plastic properties. During the last cycle of our funding we completed a series of studies culminating in the development of a well-cited, detailed biophysical model of calcium channel and vesicle co-localization that explains key features of neurotransmission at a vertebrate neuromuscular junction. We also compared the basal release and activity dependent plasticity of synapses between frog olfactory receptors and mitral cells in the main olfactory bulb to the homologous synapse in the accessory olfactory bulb (AOB). We demonstrated how the different activity dependent properties (depressing vs. facilitating) of the sensory-to-central neuron synapses of these two systems adapt them to the different sensory reception and processing tasks that are performed by these separate odour-processing circuits. During the next cycle we will extend our work on Ca2+ channel-vesicle co-localization to explore their effects on activity dependent changes in release (mouse and frog neuromuscular junction). We will extend our studies on the nose-to-AOB synapses to the next synapse in the chain, the AOB-to-amygdala. The work will address a poorly understood form of low frequency, long-term potentiation found in the lateral amygdala, which is the target of the AOB's output. Previous work on crayfish neuromuscular junction will be extended with fluorescence and electron microscopic studies of vesicle membrane recycling to address fundamental questions relating to the "life-cycle" of transmitter-containing vesicles in the presynaptic terminal. This continues the main theme of our research program; the building up of functional circuit processing capabilities from individual synaptic properties. While our NSERC program addresses the basic science of neuronal communication it also has direct implication for addressing practical issues. The majority of neurological and many neuromuscular disorders are the direct result of ddirect result of dysfunctional synaptic transmission as evidenced by the therapeutic effect of drugs that target specific steps in the transmission process. It is therefore important to understand the processes of synaptic transmission and their regulation in order to develop the information needed to decipher normal brain function and to rationally design therapeutic strategies to treat neurological disorders.