Abstract
Developing central synapses exhibit robust plasticity and undergo experience-dependent remodeling. Evidently, synapses in sensory systems such as auditory brainstem circuits mature rapidly to achieve high-fidelity neurotransmission for sound localization. This depends on a developmental switch in AMPAR composition from slow-gating GluA1-dominant to fast-gating GluA4-dominant, but the mechanisms underlying this switch remain unknown. We hypothesize that patterned stimuli mimicking spontaneous/sound evoked activity in the early postnatal stage drives this gating switch. We examined activity-dependent changes in evoked and miniature excitatory postsynaptic currents (eEPSCs and mEPSCs) at the calyx of Held synapse by breaking through the postsynaptic membrane at different time points following 2 min of theta burst stimulation (TBS) to afferents in mouse brainstem slices. We found the decay time course of eEPSCs accelerated, but this change was not apparent until > 30 min after TBS. Histogram analyses of the decay time constants of mEPSCs for naive and tetanized synapses revealed two populations centered around τfast ≈ 0.4 and 0.8 ms, but the relative weight of the τ0.4 population over the τ0.8 population increased significantly only in tetanized synapses. Such changes are blocked by NMDAR or mGluR1/5 antagonists or inhibitors of CaMKII, PKC and protein synthesis, and more importantly precluded in GluA4−/− synapses, suggesting GluA4 is the substrate underlying the acceleration. Our results demonstrate a novel form of plasticity working through NMDAR and mGluR activation to trigger a gating switch of AMPARs with a temporally delayed onset of expression, ultimately enhancing the development of high-fidelity synaptic transmission.
Highlights
Synaptic development is traditionally believed to involve an early phase of genetically directed wiring, followed by the refinement of these connections through sensory activity
Consistent with this, we have previously demonstrated that afferent simulation with a theta burst stimulation (TBS) paradigm consisting of 1 Hz bursts (50 Hz × 60 ms) for 2 min can lead to a rapid downregulation of extra−/perisynaptic N-methyl-D-aspartate receptor (NMDAR) and enhance the fidelity of neurotransmission at immature calyx of Held-medial nucleus of trapezoid body (MNTB) synapses (P < 12) [12]
Activity-dependent remodeling of synaptic AMPA receptors (AMPAR) Since the change in paired pulse ratio (PPR) may implicate a presynaptic contribution to the plasticity in evoked EPSC (eEPSC), we examined the properties of miniature EPSC (mEPSC) which can be regarded as direct readouts of postsynaptic AMPARs in response to stochastic quantal release of glutamate from many release sites at the calyx of Held terminal
Summary
Synaptic development is traditionally believed to involve an early phase of genetically directed wiring, followed by the refinement of these connections through sensory activity. Previous studies at the calyx of Held - principle neuron synapse in the medial nucleus of trapezoid body (MNTB), a glutamatergic synapse involved in the detection of interaural timing and intensity differences in the sound localization circuit, demonstrated a reorganization of postsynaptic glutamate receptors within the first 2 weeks of postnatal development. These processes involve a reduction in NMDA receptors (NMDARs) [5,6,7] paralleled by a switch from slow-gating GluA1-dominant AMPA receptors (AMPAR) to fast-gating GluA4-dominant AMPARs (2020) 13:6
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