At fast CNS synapses, the role of asynchronous release following initial synchronous release is poorly understood. We examined the contribution of asynchronous release to GABAergic transmission in the cochlear nucleus across a 40-fold range of electrical stimulus frequencies. Whereas quantal release was highly synchronized at low frequencies, it was largely continuous and desynchronized at high frequencies. Despite the change in release mode, intense and steady inhibitory transmission was virtually maintained. Experimental analyses and modeling studies indicated that this "desynchronization" process was dependent on presynaptic Ca2+ accumulation, facilitation of vesicle release, and short-term depletion of available vesicles. Asynchronous release at high frequencies may help generate a smooth inhibitory "tone" by minimizing the consequences of random timing of presynaptic action potentials.
The firing pattern of neurons is shaped by the convergence of excitation and inhibition, each with finely tuned magnitude and duration. In an auditory brainstem nucleus, glycinergic inhibition features fast decay kinetics, the mechanism of which is unknown. By applying glycine to native or recombinant glycine receptors, we show that response decay times are accelerated by addition of GABA, a weak partial agonist of glycine receptors. Systematic variation in agonist exposure time revealed that fast synaptic time course may be achieved with submillisecond exposures to mixtures of glycine and GABA at physiological concentrations. Accordingly, presynaptic terminals generally contained both transmitters, and depleting terminals of GABA slowed glycinergic synaptic currents. Thus, coreleased GABA accelerates glycinergic transmission by acting directly on glycine receptors, narrowing the time window for effective inhibition. Packaging both weak and strong agonists in vesicles may be a general means by which presynaptic neurons regulate the duration of postsynaptic responses.
_ gradient, measured using whole-cell recording. With gramicidin-perforated patch recording, E GABA was _25 ± 5 mV (mean ± S.D.), and was stable between embryonic day 17 and posthatch day 10. With normal intracellular Cl _ , GABA depolarized neurons by 12 mV.3. In current clamp, repetitive activation of the GABAergic axons reduced the probability of spiking in response to simultaneous stimulation of excitatory axons. However, IPSPs could themselves elicit action potentials, and facilitation of IPSPs by repetitive activation could lead to a characteristic pattern of spiking.4. These data indicate that IPSPs with reversal potentials positive to spike threshold may have dual functions, depending on the context of their activation.
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