| Abstract No.: | A-B1050 |
| Country: | Canada |
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| Title: | SUBUNIT COMPOSITION OF FAST-GATING AMPARS DRIVING HIGH-FIDELITY NEUROTRANSMISSION AT THE MOUSE CALYX OF HELD SYNAPSE |
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| Authors/Affiliations: | 2 Yi-Mei Yang*; 2 Jamila Aitoubah; 1 Mutsuo Nuriya; 2 Zhengping Jia; 1 Richard Huganir; 2 Lu-Yang Wang;
1 HHMI & Dept. Neuroscience, Toronto, ON, Canada, Johns Hopkins School of Medicine, Baltimore, MD, USA; 2 Program for Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
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| Content: | The calyx of Held synapse in the auditory brainstem is a critical relay synapse in the sound localization pathway and capable of reliable transmission at extraordinary rates (up to 1 kHz without failures). Biophysical and pharmacological evidence suggests that fast kinetics of AMPAR mediated excitatory postsynaptic currents (EPSCs) plays a role in enabling high-frequency neurotransmission, but the molecular composition of native AMPARs in postsynaptic principle neurons remains elusive. We hypothesize that GluR3/4 may be the primary subunit(s) at the calyx of Held synapse, as these subunits can form homomeric channels that display sub-millisecond deactivation and desensitization kinetics, reminiscent of those of native AMPARs. To test this hypothesis, we made patch-clamp recordings of evoked AMPAR-EPSCs from the calyx of Held synapse in knockout (KO) mice with either GluR3 or GluR4 gene was deleted. We found that the decay time constant of AMPAR-EPSCs was significantly increased from 0.40+0.03 ms (n=8) in wild-type (WT) mice (P16-18) to 0.92+0.07 ms (n=7) in age-matched GluR4-KO mice. In contrast, a deletion of GluR3 gene only led to a marginal increase in the decay time constant to 0.53+0.04 ms (n=4). In current-clamp configuration, we further demonstrated that slowed decay kinetics of AMPARs in GluR4-KO synapses led to elevated plateau potentials associated with repetitive synaptic activity. As a consequence, spike failures at high frequencies were significantly increased (e.g. from 0% in WT to 33.1+2.0% failures in GluR4-KO synapses during 100 ms train at 300 Hz), presumably due to partial inactivation of voltage-gated conductances by elevated plateau potentials. These observations led us to conclude that GluR4 is the main subunit of native AMPARs in postsynaptic neurons and dictates fast gating kinetics of AMPAR-EPSCs, and plays an indispensable role in preserving the fidelity of high-frequency neurotransmission at the calyx of Held synapse. |
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