Presynaptic 5-HT receptors the lower cleft glutamate concentration and alter fictive locomotion in lamprey

Networks of neurons within the central nervous system drive essential animal behaviors. Within these networks, synaptic transmission, transmitting an electrochemical pulse from one neuron to another, is the principal mechanism for transferring information. Modulation of the intensity, duration and frequency of these pulses is known to alter the output of neuronal circuits and therefore modulate behavior. Thus, to understand animal behavior, it is necessary to identify mechanisms of synaptic plasticity and determine how these mechanisms alter the activity of neuronal networks. The unique structure of the lamprey (RS) synapse makes it possible to monitor synaptic transmission by making paired electrophysiological recordings between giant un-myelinated RS axons and spinal interneurons. Previously, electrophysiological recordings have shown that activation of presynaptic 5-HT GPCRs dramatically inhibits synaptic transmission at the RS synapse through a direct action of G-betagamma on SNARE proteins that mediate vesicle fusion. The results of this thesis demonstrate that 5-HT inhibits synaptic transmission by lowering the peak concentration of synaptic cleft glutamate transients. Together, these results describe a novel pathway of presynaptic plasticity in which G-proteins regulate the synaptic cleft glutamate transient through a direct interaction with the SNARE proteins that mediate vesicle fusion.; Within the lamprey spinal cord, activation of descending reticulospinal axons drives the spinal central pattern generator that coordinates the neuronal correlate of locomotion or swimming in lamprey. The output of the central pattern generator consists of bursts of motoneurons activity that alternate across the spinal cord and may be monitored by making electrophysiological ventral root recordings. Application of 5-HT modulates central pattern generator output and prolongs the duration of ventral root bursts. The results of this thesis demonstrate that inhibition of synaptic transmission by activation of presynaptic 5-HT1D/1B receptors is sufficient to prolong ventral root bursting. These results suggest that inhibiting synaptic transmission by altering the synaptic cleft glutamate transient may modulate the output of the CPG via differential inhibition of AMPA receptors relative to NMDA receptors. Thus, this thesis reveals a novel mechanism of presynaptic plasticity, and identifies the effect of this specific type of plasticity on the neural network that drives locomotion.