Electrogenic Modulation of Signal Decoding in Presynaptic Terminals

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Presynaptic terminals are fundamental computational units in the brain, and their dysfunction is associated with several neurological diseases. They mediate the transduction of incoming electrical signals (action potentials) into chemical signals (neurotransmitter release), and the efficiency of conversion determines the strength of circuits underlying memory and behavior. The ultimate goal of this proposal is to understand the mechanisms by which presynaptic cellular machineries modulate the electro-chemical transduction of action potentials. It is known that presynaptic terminals are highly adaptive structures capable of maintaining transmission across vastly different input rates, metabolic states, and vesicle fusion probabilities. Our recent work in combination with others has exposed the fact that action potentials are not invariant signals. One critical level of regulation exists within the axonal arborization, which actively regulates the propagation and shape of electrical signals arriving at each of its presynaptic terminals. We hypothesize that a second complementary, but currently uncharacterized, set of mechanisms exist at presynaptic terminals that rapidly sense the cellular state and alter the chemical transduction of electrical signal inputs. As a result, the individual presynaptic terminals instantaneously adjust the electrogenic properties of their membranes through local ion channel activation pathways which dynamically regulate the chemical response to a given action potential as it arrives. We propose to identify the molecular basis of this “on the fly” control system of transduction in the following aims: Aim 1. We will determine how the cellular metabolic energy state of the synapse (ATP:ADP ratio) influences action potential transduction via ATP-sensitive potassium channels. Aim 2. We will determine how stimulation frequency alters the activation of presynaptic voltage- and calciumsensitive potassium channels to influence action potential transduction in excitatory and inhibitory terminals. Aim 3. We will determine how coupling calcium channels to vesicle fusion release machinery controls potassium channel activation. Results from these aims will present new data on electrogenic mechanisms influencing complex computations of presynaptic terminals, leading to a more complete understanding of synaptic plasticity and neuronal processing.