Electric Fields Due to Synaptic Currents Sharpen Excitatory Transmission

Abstract

The synaptic response waveform, which determines signal integration properties in the brain, depends on the spatiotemporal profile of neurotransmitter in the synaptic cleft. Here, we show that electrophoretic interactions between AMPA-receptor-mediated excitatory currents and negatively charged glutamate molecules accelerate the clearance of glutamate from the synaptic cleft, speeding-up synaptic responses. This phenomenon is reversed upon depolarization and diminished when intra-cleft electric fields are weakened through a decrease in the AMPA receptor density. In contrast, the kinetics of receptor-mediated currents evoked by direct application of glutamate are voltage-independent, as are synaptic currents mediated by the electrically neutral neurotransmitter GABA. Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits.Although ion currents through postsynaptic receptors are small (~10 −11 A), they can exert a lateral voltage gradient (electric field) of ~10 4 V/m inside the synaptic cleft (1, 2) raising the possibility that they can affect the dwell time of electrically charged neurotransmitters (3). Does electrodiffusion therefore play any role in synaptic transmission?The excitatory neurotransmitter glutamate is negatively charged at physiological pH (pK = 4.4), implying that postsynaptic depolarization should in principle retard its escape from the synaptic cleft (Fig. 1, A). AMPA-receptor-mediated excitatory postsynaptic currents (AMPAR EPSCs) decay more slowly at positive than at negative holding voltages in hippocampal basket cells (4) and in cerebellar granule cells (5). However, this has not been reported for AMPAR EPSCs generated at perisomatic synapses on CA1 or CA3 pyramidal cells (6-8). We evoked dendritic AMPAR EPSCs in CA1 pyramidal cells by stimulating Schaffer collaterals: the EPSC decay time ⊺ (defined here as the area/peak ratio) increased monotonically with depolarization ( Fig. 1, B). The ratio between ⊺ recorded at +40 mV and at −70 mV (⊺ +40 / ⊺ −70 ) was consistently above one (average ± SEM: 2.17 ± 0.09, n = 49, p < 0.001; fig. S1, A). This asymmetry was independent of the EPSC amplitude, glutamate transport or recording temperature, and could not be accounted for by unknown voltagedependent properties of receptor antagonists ( fig. S1, A A trivial possible explanation for this phenomenon is that AMPARs themselves have voltage-dependent kinetics. This has indeed been reported for AMPARs activated by brief pulses of glutamate applied to outside-out patches excised from brainstem neurons (9, 10), but not from hippocampal or dentate granule neurons (11). We confirmed that the decay of AMPAR currents evoked by 1 ms / 1 mM glutamate pulses in outside-out patches excised from somata (n = 9) or dendrites (n = 6) of CA1 pyramidal cells was indistinguishable at positive and negative voltages. Symmetrical decay kinetics were also observed when the AMPAR density was decreased in the patch with 0.1 μM NBQX (Fig. 1, C)...

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