“In the past, regulation of synaptic responses was assumed to be largely due to postsynaptic variables, and the transmitter was a constant,” Lu says. “We are saying that the transmitters may also vary significantly in composition.”
A major inhibitory neurotransmitter of the auditory pathway is glycine. The binding of glycine to its receptors briefly prevents a synapse from being activated. This inhibitory effect is thought to help the brain interpret the relative timing and intensity of signals from either ear.
Another inhibitory transmitter, called GABA, is expressed in many of the same glycine-sensitive synapses and is packaged together and coreleased with glycine in several areas of the brain. GABA is a weak agonist of the glycine receptor, but it is too weak to activate the receptor by itself. GABA also has its own receptors, so the significance of the corelease has been controversial.
To address this question, the authors applied glycine with and without GABA to isolated membrane patches containing only glycine receptors. Glycine's inhibition of postsynaptic neuronal signaling was shortened in the presence of physiological levels of GABA. More GABA caused an even faster loss of inhibitory power.
In vivo, the two transmitters occurred together in over half the presynaptic terminals in the examined auditory region. When the authors blocked synaptic uptake of GABA precursors, the acceleration effect diminished. When they mimicked the action of the glycine receptor by applying blocking currents to an auditory neuron, they found that a small change in the decay rate of the inhibitory signal had a large effect on the neuron: a 1-ms reduction in the decay constant cut the neuron's inhibition window from 4 to 2 ms.
Questions remaining include how the ratio of the two transmitters is regulated and whether that ratio varies among synapses and over time. “We expect to see a wide variation in relative concentrations of the two,” Trussell says, matched to the individual needs of the synapse.