7. Writing the Lives of Animals

Non-technical summary Localization of sound sources in the azimuth, which makes use of interaural differences in timing and/or intensity of acoustic signals, is of vital importance for most mammals. Using the small differences in time of arrival and/or intensity at the two ears requires that propagation of electric pulses in the auditory system be temporally precise. In this study, we found that elimination of GluA4, a protein particularly abundant in auditory cells, significantly impairs their ability to faithfully transmit electric signals, leading to profound deficits in auditory responses to sound stimuli in mice. Therefore, we conclude that GluA4 is indispensable for enabling information flow with high fidelity in the auditory circuitry. Our work has identified GluA4 as a potential molecular candidate involved in human hearing deficits and disorders.Abstract Fast excitatory synaptic transmission in central synapses is mediated primarily by AMPA receptors (AMPARs), which are heteromeric assemblies of four subunits, GluA1-4. Among these subunits, rapidly gating GluA3/4 appears to be the most abundantly expressed to enable neurotransmission with submillisecond precision at fast rates in subsets of central synapses. However, neither definitive identification of the molecular substrate for native AMPARs in these neurons, nor their hypothesized functional roles in vivo has been unequivocally demonstrated, largely due to lack of specific antagonists. Using GluA3 or GluA4 knockout (KO) mice, we investigated these issues at the calyx of Held synapse, which is known as a high-fidelity synapse involved in sound localization. Patch-clamp recordings from postsynaptic neurons showed that deletion of GluA4 significantly slowed the time course of both evoked and miniature AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), reduced their amplitude, and exacerbated AMPAR desensitization and short-term depression (STD). Surprisingly, presynaptic release probability was also elevated, contributing to severe STD at GluA4-KO synapses. In contrast, only marginal changes in AMPAR-EPSCs were found in GluA3-KO mice. Furthermore, independent of changes in intrinsic excitability of postsynaptic neurons, deletion of GluA4 markedly reduced synaptic drive and increased action potential failures during high-frequency activity, leading to profound deficits in specific components of the auditory brainstem responses associated with synchronized spiking in the calyx of Held synapse and other related neurons in vivo. These observations identify GluA4 as the main determinant for fast synaptic response, indispensable for driving high-fidelity neurotransmission and conveying precise temporal information.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GluA4 is indispensable for driving fast neurotransmission across a high‐fidelity central synapse

Yang

Aitoubah

Lauer³

et al. 2011

“…Previous studies revealed that BCs show fast electrical signalling at multiple levels (Jonas et al 2004). BCs receive a fast excitatory synaptic input, which allows them to detect coincident excitation of pyramidal neurons (Miles, 1990;Geiger et al 1997;Galarreta & Hestrin, 2001). BCs are able to generate high-frequency trains of APs during sustained current injection in vitro (Rudy & McBain, 2001) and during theta-gamma activity in vivo (Bragin et al 1995;J Physiol 586.8 Penttonen et al 1998;Csicsvari et al 2003).…”

mentioning

confidence: 99%

Efficient Ca²⁺ buffering in fast‐spiking basket cells of rat hippocampus

Aponte

Bischofberger

Jónás

2008

“…Slow EPSPs in interneurons were shown to permit greater integration of signals from separate synaptic inputs, resulting in variably timed spike outputs (Maccaferri & Dingledine, 2002) which would mediate prolonged but imprecise inhibition of principal cell dendrites. This contrasts with parvalbumin-expressing, somatically synapsing basket cells, which have fast EPSCs (Geiger et al 1997) and are specialised to coordinate precisely timed spiking activity in principal cells (Pouille & Scanziani, 2001;Bartos et al 2002).…”

Section: Discussionmentioning

confidence: 97%

Plasticity of NMDA receptor‐mediated excitatory postsynaptic currents at perforant path inputs to dendrite‐targeting interneurons

Harney

Anwyl

2012

Key points• NMDA receptors (NMDARs) activated by the neurotransmitter glutamate underlie certain forms of synaptic plasticity in the brain.• These receptors are also subject to plasticity and we have previously described both long-term potentiation (LTP) and long-term depression (LTD) of NMDARs in the principal granule cells of the dentate gyrus region of hippocampus.• The functional significance of these changes in NMDARs on hippocampal network activity depends on whether this occurs only on principal, excitatory neurons or if it also occurs on inhibitory interneurons.• Here we demonstrate differences in NMDAR subtype expression and plasticity in dendrite-targeting interneurons compared to granule cells.• Interneurons displayed LTD of NMDAR-mediated synaptic transmission in response to perforant path activation and had a high threshold for induction of LTP of NMDAR-mediated synaptic currents, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.Abstract Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B-and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms