Impaired auditory processing and altered structure of the endbulb of Held synapse in mice lacking the GluA3 subunit of AMPA receptors

Abstract

AMPA glutamate receptor complexes with fast kinetics conferred by subunits like GluA3 and GluA4 are essential for temporal precision of synaptic transmission. The specific role of GluA3 in auditory processing and experience related changes in the auditory brainstem remain unknown. We investigated the role of the GluA3 in auditory processing by using wild type (WT) and GluA3 knockout (GluA3-KO) mice. We recorded auditory brainstem responses (ABR) to assess auditory function and used electron microscopy to evaluate the ultrastructure of the auditory nerve synapse on bushy cells (AN-BC synapse). Since labeling for GluA3 subunit increases on auditory nerve synapses within the cochlear nucleus in response to transient sound reduction, we investigated the role of GluA3 in experience-dependent changes in auditory processing. We induced transient sound reduction by plugging one ear and evaluated ABR threshold and peak amplitude recovery for up to 60 days after ear plug removal in WT and GluA3-KO mice. We found that the deletion of GluA3 leads to impaired auditory signaling that is reflected in decreased ABR peak amplitudes, an increased latency of peak 2, early onset hearing loss and reduced numbers and sizes of postsynaptic densities (PSDs) of AN-BC synapses. Additionally, the lack of GluA3 hampers ABR threshold recovery after transient ear plugging. We conclude that GluA3 is required for normal auditory signaling, normal ultrastructure of AN-BC synapses in the cochlear nucleus and normal experience-dependent changes in auditory processing after transient sound reduction.

Synaptic plasticity through activation of GluA3-containing AMPA-receptors

“…GluA3-deficient mice show a number of physiological and behavioral abnormalities, which may putatively depend on GluA2/3-plasticity in different brain regions. For instance, GluA3-deficient mice show increased social and aggressive behavior ( Adamczyk et al, 2012 ), a reduced alcohol-seeking behavior ( Sanchis-Segura et al, 2006 ), impaired auditory processing ( García-Hernández et al, 2017 ), and altered electroencephalographic patterns in the cortex during sleep ( Steenland et al, 2008 ). Based on the findings in this study, we examined the role of GluA3-dependent plasticity at synapses onto Purkinje cells (PCs) of the cerebellum ( Gutierrez-Castellanos et al, 2017 ).…”

Role of GluA3 AMPA Receptor Subunits in the Presynaptic and Postsynaptic Maturation of Synaptic Transmission and Plasticity of Endbulb−Bushy Cell Synapses in the Cochlear Nucleus

“…Brain slices were obtained from CD57B6J WT mice (n ϭ 21 animals) and GluA3 KO mice (n ϭ 21 animals) of both sexes, aged from postnatal day (P) 17 to P21. GluA3 KO mice were kindly provided by Dr. Sakimura (García-Hernández et al, 2017). Genotyping of these mice was also confirmed post hoc.…”

“…Anatomical studies suggest that the GluA3 subunit plays a preponderant role in activity-dependent plasticity (Whiting et al, 2009;Wang et al, 2011;Clarkson et al, 2016) and normal auditory processing (García-Hernández et al, 2017). Upregulation of GluA3, but not GluA4, is believed to underlie hearing recovery after transient hearing loss (Clarkson et al, 2016;García-Hernández et al, 2017). However, the specific role of GluA3 in the synaptic transmission in endbulb synapses remains unexplored.…”

“…However, the specific role of GluA3 in the synaptic transmission in endbulb synapses remains unexplored. Loss of GluA3 decreases the amplitude and increases the latency of wave II of the auditory brainstem responses (García-Hernández et al, 2017), suggesting that activity in the cochlear nucleus has been altered. Furthermore, loss of GluA3 produces ultrastructural changes in presynaptic and postsynaptic terminals of endbulb synapses (García-Hernández et al, 2017;Rubio et al, 2017).…”

“…Loss of GluA3 decreases the amplitude and increases the latency of wave II of the auditory brainstem responses (García-Hernández et al, 2017), suggesting that activity in the cochlear nucleus has been altered. Furthermore, loss of GluA3 produces ultrastructural changes in presynaptic and postsynaptic terminals of endbulb synapses (García-Hernández et al, 2017;Rubio et al, 2017). These changes will have consequences on synaptic efficacy and plasticity (Taschenberger et al, 2002;Cathala et al, 2005;Freche et al, 2011;Allam et al, 2015), a hypothesis that we address in this study by investigating synaptic transmission and short-term plasticity in endbulb synapses of GluA3 KO and WT mice.…”