Neuroscience 285 (2015) 248–259

NEUROSCIENCE FOREFRONT REVIEW FROM DEVELOPMENT TO DISEASE: DIVERSE FUNCTIONS OF NMDA-TYPE GLUTAMATE RECEPTORS IN THE LOWER AUDITORY PATHWAY J. T. SANCHEZ, a,b,c* S. GHELANI d AND S. OTTO-MEYER d

Ó 2014 The Authors. Published by Elsevier Ltd. on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

a

Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, United States b

The Hugh Knowles Hearing Research Center, United States

c

Northwestern University Interdepartmental Neuroscience Program, United States d

Key words: auditory development, auditory disease, glutamate, hearing, N-methyl-D-aspartate receptors.

Weinberg College of Arts & Sciences, United States

Contents Introduction 248 NMDA-Rs in the lower auditory pathway of mammals and avians 249 Mammalian inner hair cell-spiral ganglion neuron (IHC-SGN) synapse 249 Cochlear nucleus 250 Mammalian ventral cochlear nucleus (VCN) and the avian cochlear nucleus magnocellularis (NM) 250 Mammalian dorsal cochlear nucleus (DCN) 251 Binaural circuits 252 Mammalian MNTB 252 Mammalian MSO 253 Avian NL 253 Mammalian LSO 254 Lateral lemniscus 254 Inferior colliculus 255 Conclusion 256 Disclosures 256 Acknowledgments 256 References 256

Abstract—N-methyl-D-aspartate receptors (NMDA-Rs) are located at each synapse in the lower auditory pathway of mammals and avians. Characterized by a slow and long-lasting excitatory response upon glutamate activation, their existence in a sensory system biologically engineered for speed and precision seems counterintuitive. In this review we consider the diverse functions of NMDA-Rs. Their developmental regulation and unique subunit composition in the inner ear promote protective and neurotrophic roles following acute insult by regulating AMPA-R expression and assisting in the restoration of synaptic inputs. This contrasts with chronic damage where overactivation of NMDARs is implicated in neuronal death. These functions are thought to be involved in auditory diseases, including noise-induced hearing loss, neural presbycusis, and tinnitus via aberrant excitation. A more traditional role emerges in the developing auditory brainstem, where NMDA-Rs are downregulated and switch subunit composition with maturation. Their biophysical properties also contribute to synaptic dynamics resembling long-term plasticity. At mature synapses they support reliable auditory processing by increasing the probability of action potential generation, regulating first-spike latency, and maintaining reliable action potential firing. Thus, NMDA-R functions in the lower auditory pathway are diverse, contributing to synaptic development, plasticity, temporal processing, and diseases.

INTRODUCTION Glutamate is the primary excitatory neurotransmitter in the brain, including the auditory system of mammals and avians. When released from presynaptic terminals, it binds to postsynaptic AMPA- and N-methyl-D-aspartatereceptors (AMPA-Rs and NMDA-Rs, respectively). The fast and temporally precise encoding of sound is heavily dependent on synaptic AMPA-Rs (Trussell, 1998; Parks, 2000). NMDA-R responses however, are slower and longer lasting than AMPA-Rs and although NMDA-Rs’ presence suggests a functional role in hearing, their properties do not appear beneficial to a system designed for speed and reliability. In this review, we consider the role of NMDA-Rs in the auditory system by following the ascending pathway from the inner ear to the midbrain

*Correspondence to: J. T. Sanchez, 2240 Campus Drive, Northwestern University, Evanston, IL 60208, United States. E-mail address: [email protected] (J. T. Sanchez). Abbreviations: AMPA-R, a-amino-3-hydroxy-4-isoxazolepropionic acid-type glutamate receptor; DCN, dorsal cochlear nucleus; DNLL, dorsal nucleus of the lateral lemniscus; GABA, c-aminobutyric acid; ICX, external nucleus of the inferior colliculus; IHC, inner hair cell; LSO, lateral superior olive; LTD, long-term depression; LTP, long-term potentiation; mGluR, metabotropic glutamate receptors; MNTB, medial nucleus of the trapezoid body; MSO, medial superior olive; NL, nucleus laminaris; NM, nucleus magnocellularis; NMDA-R, N-methyl-Daspartate receptor; SGN, spiral ganglion neuron; VCN, ventral cochlear nucleus.

http://dx.doi.org/10.1016/j.neuroscience.2014.11.027 0306-4522/Ó 2014 The Authors. Published by Elsevier Ltd. on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 248

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(Fig. 1). We highlight NMDA-Rs’ diverse role in auditory synaptic development, plasticity, and temporal processing, and discuss their contribution to auditory diseases, including noise-induced hearing loss, neural presbycusis, and peripheral tinnitus.

Malenka, 2012; Bartlett and Wang, 2013; Paoletti et al., 2013; Sanz-Clemente et al., 2013). Mammalian inner hair cell-spiral ganglion neuron (IHC-SGN) synapse Sound is transmitted to the central auditory system in the form of action potentials via the auditory nerve. Type I SGNs make up 90% of nerve fibers and their dendrites exclusively contact the base of IHCs in the cochlea. At the mammalian IHC-SGN synapse, NMDARs are present in early auditory development and studies show a transient expression of GluN1 and GluN2A subunits (Knipper et al., 1997). With maturation, there is a strong reduction in GluN1 expression, a complete elimination of GluN2A (Knipper et al., 1997; Ruel et al., 2008), and an increase in GluN2B, C and D subunits (Puel, 1995; Ruel et al., 2008). This is opposite from other developing auditory nuclei where GluN2B is downregulated and GluN2A is upregulated. As such, NMDA-Rs are not directly involved in glutamatergic transmission at IHC-SGN synapses (Puel et al., 1991, 2002; Ruel et al., 1999). Physiological recordings show a lack of NMDA-R responses, despite removal of magnesium blockade and application of the co-agonist glycine (Glowatzki and Fuchs, 2002). Instead, NMDA-Rs are thought to contribute to the regulation of surface AMPA-R expression, since Chen et al. (2007) found a decrease in expression of surface AMPA-Rs upon application of an NMDA-R agonist. This decrease in AMPAR expression was blocked by the application of NMDA-

NMDA-RS IN THE LOWER AUDITORY PATHWAY OF MAMMALS AND AVIANS NMDA-Rs are ligand-gated and voltage-dependent cation channels permeable to sodium, potassium, and calcium ions. They are activated by glutamate and the co-agonist glycine. At negative membrane potentials NMDA-Rs are blocked by extracellular magnesium, requiring AMPA-R depolarization to relieve this block. NMDA-R composition includes the mandatory GluN1 subunit and a variety of GluN2A, B, C, and D subunits. NMDA-Rs containing GluN2A are characterized by fast response kinetics (lasting tens of milliseconds), while NMDA-Rs containing GluN2B are characterized by slow response kinetics (lasting hundreds of milliseconds). The GluN2B subunit usually dominates at auditory synapses during early development while more mature synapses contain the GluN2A subunit. All of these features however, are not always shared in the lower auditory pathway, providing a unique platform to examine diverse NMDA-R functions as they relate to hearing. Readers interested in general NMDA-R function elsewhere in the brain are referred to the following reviews (Traynelis et al., 2010; Luscher and

To Higher Auditory Regions Midline

ICX

ICX

Inferior Colliculus

IC

IC

DNLL

+

+

DNLL

Lateral Lemniscus

+ +

DCN

+ IHC

MNTB

+

+

+ IHC

LSO

Olivary Complex

VCN Cochlear Nucleus

MSO

- Superior -

+

SGN

MSO

LSO

+

+

DCN

VCN MNTB

Cochlear Nucleus

+ + SGN

+

Fig. 1. Schematic representation of the mammalian lower auditory pathway. Sound is converted into electrical activity by inner hair cells (IHC) of the cochlea. Neural action potentials are generated by spiral ganglion neurons (SGN) of the vestibulocochlear cranial nerve VIII. Action potential activity is sent along the ascending central auditory pathway that includes the cochlear nucleus (CN) and superior olivary complex (SOC) located in the lower pons, the lateral lemniscus (LL) located in the brainstem, and the inferior colliculus (IC) located in the midbrain. Processed information is then sent to higher auditory regions including the medial geniculate body (located in the thalamus) and the auditory cortex (not shown). The CN contains the ventral and dorsal cochlear nuclei (VCN and DCN, respectively). The SOC contains the lateral superior olive, medial superior olive, and medial nucleus of the trapezoid body (LSO, MSO, and MNTB, respectively). Specific subregions of the superior olivary complex are omitted for clarity. The lateral lemniscus contains several nuclei but of interest for this review is the dorsal nucleus (DNLL). The IC contains the external nucleus (ICX, most prominent in avians). Blue lines and plus symbols indicate excitatory pathway. Red lines and minus symbols represents inhibitory pathways. Dashed lines are used to clarify binaural pathways. For comparison, a portion of the mammalian VCN and MSO are analogous in structure and function to the avian nucleus magnocellularis (NM) and nucleus laminaris (NL), respectively.

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R antagonists and the exclusion of calcium from extracellular solution. Acute insult (via temporary noise exposure) also caused a reversible loss in hearing sensitivity and reduction in surface AMPA-R expression. In the presence of NMDA-R antagonists, acute insult induced a smaller decrease in hearing sensitivity, faster recovery from loss, and a smaller reduction in surface AMPA-R expression (Chen et al., 2007). NMDA-Rs may therefore protect SGNs from acute insult during temporary noise exposure through the reduction of surface AMPA-R expression. Following acute insult, SGN dendrites reconnect to their IHC targets (Zheng et al., 1997; Wang and Green, 2011) and studies suggest that NMDA-Rs play a neurotrophic role in this restoration process (Pujol and Puel, 1999). In experiments by Puel et al. (1995), recovery of cochlear function was observed just days following acute insult. The return to normal cochlear function was accompanied by regenerating SGN dendrites onto IHCs reminiscent of early developing synapses (Puel et al., 1995). Blocking NMDA-Rs delayed the regrowth and formation of synapses, as well as the restoration of cochlear function (d’Aldin et al., 1997). Such neurotrophic roles for NMDA-Rs during periods of synaptogenesis are well documented elsewhere in the brain (Burgoyne et al., 1993). Recent studies however, show low-levels of temporary noise exposure also cause irreversible loss and atrophy of SGNs despite complete recovery of cochlear function (Kujawa and Liberman, 2009; Lin et al., 2011). It is not clear what role NMDA-Rs have, if any, in this scenario. In neural presbycusis, an age-related hearing loss resulting from atrophy of neurons in the lower auditory pathway (Schuknecht and Gacek, 1993), studies show significant increases in expression of GluN1-containing NMDA-Rs at IHC-SGN synapses of aging animals (Tang et al., 2014). The upregulation of GluN1-containing NMDA-Rs could be an attempt to compensate for loss of SGNs observed with neural presbycusis through restoration of synaptic contacts (Peng et al., 2013). Thus, NMDA-Rs appear to play a neurotrophic role during aging, similar to what is seen following acute insult during temporary noise-exposure. Permanent noise-induced hearing loss is often caused by chronic damage to the cochlea. As opposed to the protective role NMDA-Rs play during acute insult, blocking NMDA-Rs help to prevent chronic damage in the cochlea (Puel, 1995; Duan et al., 2000). One explanation suggests that during chronic damage, an increase in glutamate release from IHCs activates NMDA-Rs and triggers excessive calcium in SGN dendrites. The resulting overexcitation increases ATP demand and correspondingly increases reactive oxygen species in SGN neurons (Sahley et al., 2013). Excessive calcium influx through NMDA-Rs therefore results in a cascade of metabolic events including free-radical production, protease and endonuclease activation, and eventually neuronal death (Reynolds and Hastings, 1995). NMDA-Rs also play a role in the generation of tinnitus, broadly defined as the perception of sound within the ear when no external sound is present. The chemical induction of tinnitus through the action of salicylate

(active compound of aspirin) is alleviated when NMDARs are blocked (Guitton et al., 2003), indicating that salicylate induces tinnitus through its ability to modulate NMDA-R function. A proposed mechanism suggests salicylate causes overactivation of NMDA-Rs and susceptibility of SGNs to aberrant excitation, generating symptoms associated with tinnitus (Guitton, 2012). Salicylate-induced tinnitus is often short term and recovery can be complete. This contrasts noise-induced or age-related tinnitus, which is often long term and has no known cure. However, studies show that blocking the GluN2B subunit within 4 days following noise exposure reduced behavioral signs of tinnitus for up to 2 weeks (Guitton and Dudai, 2007; Brozoski et al., 2013). When GluN2B was blocked 8–12 days following noise exposure, behavioral signs of tinnitus returned. This suggests noiseinduced tinnitus undergoes a consolidation period lasting several days during which time; GluN2B-containing NMDA-Rs play a critical role in its generation. (Guitton and Dudai, 2007). If NMDA-Rs contribute to tinnitus symptoms, it is conceivable to envision a feed-forward mechanism. NMDA-Rs are upregulated following acute insult due to their neurotrophic role, further contributing to overactivation upon chronic damage, which in turn upregulates more NMDA-Rs, thereby exacerbating the symptoms of tinnitus via abnormal spontaneous firing of SGNs. The pathophysiological role of NMDA-Rs in the creation of tinnitus suggests antagonists of this glutamate receptor constitute pharmacological candidates for the treatment of tinnitus in humans (Simpson and Davies, 1999). Indeed, current human clinical trials are testing NMDA-R antagonists as possible treatments for tinnitus (van de Heyning et al., 2014). Overall, NMDA-R function at IHC-SGN synapses is unique. With maturation there is a significant downregulation of the GluN2A subunit. This is opposite from most other developing auditory nuclei where GluN2B is reduced. Unlike elsewhere in the lower auditory pathway, NMDA-Rs are not involved in glutamatergic transmission, which is exclusively dependent on AMPA-Rs. Instead, NMDA-Rs are thought to regulate surface AMPA-R expression and assist in restoring synaptic inputs following acute insult. Overactivation of NMDA-Rs and subsequent calcium influx during chronic damage contributes to permanent noise-induced hearing loss, neural presbycusis, and tinnitus via aberrant excitation of the auditory nerve (Table 1). Cochlear nucleus Mammalian ventral cochlear nucleus (VCN) and the avian cochlear nucleus magnocellularis (NM). At the first brainstem synapse, NMDA-Rs are located in the mammalian VCN and the analogous avian cochlear NM. Neurons in VCN and NM reliably process auditory information through specialized endbulb of Held synapses (Adams, 1986; Carr and Boudreau, 1991;

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J. T. Sanchez et al. / Neuroscience 285 (2015) 248–259 Table 1. NMDA-Rs at the mammalian IHC-SGN synapse Condition

Cause

Suggested contribution

Source

Temporary noise-induced hearing loss

Acute insult

Neural presbycusis

Aging

Permanent noise-induced hearing loss Tinnitus

Chronic damage

Regulate surface AMPA-R expression (protective) Restoration of inputs (neurotrophic) GluN1 upregulation? GluN1 upregulation Neurotrophic? Excitotoxic? Overactivation and calcium influx (excitotoxic)

Chen et al. (2007) Puel et al. (1998) ? Tang et al. (2014) Peng et al. (2013) ? Puel (1995) and Duan et al. (2000)

Overactivation and calcium influx (excitotoxic) Aberrant excitability of auditory nerve fibers

Guitton et al. (2003) Guitton and Dudai (2007) Ruel et al. (2008) Guitton (2012) Sahley et al. (2013) Brozoski et al. (2013)

Salicylate (aspirin) Acute insult Chronic damage Aging

?, Suggested NMDA-R contribution not known.

Koppl, 1994). Numerous endbulb synapses are eliminated during development such that only two or three large terminals contact one cell body (Jhaveri and Morest, 1982; Ryugo et al., 2006; Lu and Trussell, 2007). This synaptic pruning takes place during a time period when GluN2B-containing NMDA-R responses dominate (Bellingham et al., 1998; Lu and Trussell, 2007). In the avian NM, developing endbulb synapses destined for elimination have larger NMDA-R responses compared to AMPA-Rs (Lu and Trussell, 2007). These NMDA-R responses have slower kinetics and studies suggest they lack the GluN2A subunit (Lu and Trussell, 2007), a result similar to the mammalian IHC-SGN synapse. Others however, have shown that GluN2B mRNA is high early in development and declines with maturation, Dual-Component Excitatory Postsynaptic Potential (EPSP) AMPA-R NMDA-R 5 mV 5 ms

RMP -60 mV

Dual-Component Excitatory Postsynaptic Current (EPSC) VCLAMP -20 mV

while GluN2A mRNA increases with maturation and remains elevated into adulthood (Tang and Carr, 2007). These conflicting results illustrate differences between mRNA expression levels and synaptic function. While changes in subunit composition may occur, this switch does not functionally happen at synapses. A functional consequence of this lack in subunit switch may restrict surface AMPA-R expression – as seen at the mammalian IHC-SGN synapses and elsewhere in the brain (Haas et al., 2006). Mature endbulb synapses have excitatory responses composed of two pharmacologically and kinetically distinct components: an early AMPA-R response lasting less that one millisecond and a late NMDA-R response lasting several tens of milliseconds (Fig. 2) (Zhang and Trussell, 1994a; Pliss et al., 2009). NMDA-R response kinetics do not change into adulthood and suggest the dominance of a particular subunit type, but it is not clear which functional subunit(s) prevails (Pliss et al., 2009). Although NMDA-R responses account for a small percentage of the total peak conductance at mature endbulb synapses, (Zhang and Trussell, 1994b; Pliss et al., 2009), the receptor is still integral in auditory processing (Pliss et al., 2009). NMDA-Rs contribute to an increased probability of action potential firing, shorter first-spike latency, and reduced action potential jitter. These results are highly dependent on stimulus condition but indicate mature NMDA-R function supports the conveying of precise temporal information in the cochlear nucleus.

NMDA-R

AMPA-R

200 pA 5 ms

Fig. 2. Dual component glutamatergic responses in the lower auditory pathway of mammals and avians. Representative traces of dual component excitatory responses show fast and slow phases mediated by AMPA-Rs and NMDA-Rs, respectively. Top trace represents in vitro excitatory postsynaptic potential (EPSP) recorded in current-clamp configuration following afferent stimulation. Bottom trace represents in vitro excitatory postsynaptic current (EPSC) recorded in voltage-clamp configuration following afferent stimulation. RMP = resting membrane potential. VCLAMP = membrane voltage at which the neuron was held.

Mammalian dorsal cochlear nucleus (DCN). The DCN is a region of the mammalian cochlear nucleus responsible for integrating complex auditory and multisensory inputs (Bell, 2002; Oertel and Young, 2004). DCN fusiform neurons and cartwheel interneurons express NMDA-Rs mainly at their apical dendrites, where parallel fibers arising from granule neurons make contact (Bilak et al., 1996). In contrast, very few (if any) NMDA-Rs are expressed at fusiform basal dendrites where SGN inputs are located (Fig. 3) (Bilak et al., 1996). With maturation there is a decrease in GluN1 and GluN2B subunits and an increase in GluN2A-containing NMDA-Rs (Joelson

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LTP/LTD NMDA-Rs present parallel fiber

LTP/LTD apical dendrites

+

+

Fusiform Neuron Cartwheel Neuron

Granule Neuron NMDA-Rs not present?

axon from multiple sources

basal dendrites No LTP/LTD

+

SGN axon

+

DCN

IHC

+ + SGN

VCN Cochlear Nucleus

Fig. 3. Simplified schematic representation of the neural circuitry of the dorsal cochlear nucleus. NMDA-Rs in the mammalian DCN contribute to synaptic plasticity resembling LTP and LTD. The DCN is a sub region of the cochlear nucleus responsible for integrating complex auditory and multisensory inputs. In the DCN, fusiform neurons and cartwheel interneurons contain NMDA-R expression mainly at their apical dendrites. Parallel fibers arising from granule neurons make synaptic contact with these apical dendrites, where NMDA-R-dependent LTP and LTD can be induced. In contrast, very few (if any) NMDA-Rs are expressed at fusiform basal dendrites, the point at which SGNs make their synaptic contact and where LTP and LTD cannot be induced. Blue lines and plus symbols represent excitatory inputs.

and Schwartz, 1998), indicating a downregulation of NMDA-Rs with the classic subunit switch from GluN2B to GluN2A. A clear function exists for NMDA-Rs on apical dendrites in the DCN, where they contribute to longterm synaptic plasticity. At parallel fiber synapses onto fusiform and cartwheel neurons (Fig. 3), long-term synaptic plasticity is induced through spiketime-dependent protocols (Tzounopoulos et al., 2004). Excitatory postsynaptic potentials (EPSPs) preceding action potentials result in long-term potentiation (LTP) in fusiform neurons, but long-term depression (LTD) in cartwheel neurons. LTP and LTD are blocked by the application of an NMDA-R antagonist in both neuron types, indicating NMDA-R dependence. NMDA-R-dependent

potentiation cannot be induced by stimulation of SGN inputs (Fig. 3), consistent with studies indicating a small number of NMDA-Rs on basal dendrites (Bilak et al., 1996). Although a low level of NMDA-R conductance remains at maturation when SGN inputs are stimulated, its functional role is not known (Fujino and Oertel, 2003). LTP and LTD are also induced through high- and lowfrequency tetanic stimulation, respectively (Fujino and Oertel, 2003) Using this protocol, blocking NMDA-Rs eliminated LTD in cartwheel neurons. Conversely, LTP/ LTD in fusiform neurons and LTP in cartwheel neurons is reduced but not completely eliminated when NMDARs are blocked. Similar reductions are seen upon application of metabotropic glutamate receptor (mGluR) antagonists where blockade of mGluRs further reduces synaptic plasticity, but does not eliminate it. This implies NMDA-Rs only partially contribute to induction of LTP and LTD (with the possible exception of cartwheel LTD), with mGluRs and other channels providing additional methods of induction. Buffering internal calcium levels completely eliminated long-term plasticity in all cases, indicating calcium influx through NMDA-Rs is a likely mechanism for their contribution to long-term plasticity in the DCN. The functional role of synaptic plasticity in the DCN has yet to be determined but one possibility is to maintain a balance between excitation and inhibition, as activity-dependent mechanisms alter synaptic strength in the DCN (Tzounopoulos, 2008). Overall, NMDA-Rs in the VCN and DCN are downregulated and their responses become faster, consistent with a developmental switch in subunit composition. Functional studies in the avian NM challenge these findings. NMDA-R responses here are downregulated but lack developmental changes in response kinetics and their pharmacological profile suggests GluN2B subunit dominance; a process thought necessary to eliminate inappropriate endbulb synapses. NMDA-Rs in mature VCN do not show evidence of synaptic plasticity, while specific neural types in the DCN exhibit long-term plasticity in the form of both LTP and LTD – a process partly dependent on NMDA-R activation. Binaural circuits Binaural circuits in mammals and avians include the medial superior olive (MSO), the analogous avian nucleus laminaris (NL), the lateral superior olive (LSO), and the medial nucleus of the trapezoid body (MNTB). These nuclei are responsible for binaural computations used for sound source localization. Mammalian MNTB. Mammalian MNTB neurons receive a single excitatory input from the VCN via a specialized calyx synapse. During development of this synapse, excitatory responses are mediated by early AMPA-R and late NMDA-R components (Forsythe and Barnes-Davies, 1993; Caicedo and Eybalin, 1999; Hoffpauir et al., 2006). Consistent among studies is the developmental downregulation of NMDA-R responses and a quickening of their kinetics. This is attributed to a switch from GluN2B to GluN2A subunits, as studies show

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Mammalian MSO. The mammalian MSO encodes time disparities on the order of microseconds as sound arrives from the two ears, providing cues used for sound localization. It receives bilateral excitatory inputs from the VCN that mostly target segregated dendrites of MSO neurons, while inhibitory inputs from the ipsilateral MNTB mostly target MSO cell bodies (Grothe et al., 2010). NMDA-Rs mediate slow excitatory responses at developing MSO synapses (Smith et al., 2000) but their regulation and subunit composition are not known. The segregation of excitatory and inhibitory inputs at mature MSO synapses is not strictly compartmentalized and NMDA-Rs here have a defined role (Couchman et al., 2012). NMDA-Rs are biased to the cell body and their activation resembles that of extrasynaptic receptors, driven by strong excitatory and inhibitory inputs. By combining glutamate uncaging and afferent fiber stimulation, Couchman et al. (2012) showed that glycine spillover from inhibitory MNTB-MSO synapses activates somatic NMDA-Rs, providing direct evidence for an interaction between NMDA-Rs and glycinergic inputs from the MNTB. This observation suggests an activity-dependent role of NMDA-Rs in the mature MSO; during periods of high activity, extrasynaptic NMDA-Rs increase leak conductance and reduce the time constant of MSO neurons, shortening the window when inputs can summate for accurate binaural computation. Avian NL. NL is analogous in form and function to the mammalian MSO. Bilateral excitatory inputs from NM target segregated NL dendrites, where time disparities from the two ears are used to determine sound source localization. Unlike the mammalian MSO however, several studies have characterized the developmental profile of NMDA-Rs in NL. Studies show developmental changes in NMDA-R expression (Tang and Carr, 2004, 2007) and quickening of their responses indicates a developmental switch in subunit composition (Fig. 4A, B) (Sanchez et al., 2010, 2012). NMDA-R responses peak around hearing onset and are dramatically reduced with maturation (Fig. 4C). Prior to this downregulation, NMDA-Rs limit action potential output of NL neurons by summating responses that prevent sodium channel de-inactivation, due to the slow time course of GluN2Bcontaining receptors. When considering the binaural innervation NL neurons receive, summating NMDA-R

A

NMDA-REPSC Before

After

VCLAMP +40 mV

B

20 ms

Rel: Hearing Onset

+2BBLOCK

100

0

Before After Rel: Hearing Onset

Developmental Switch in Subunit Content

GluN1 + GluN2B Before

GluN1 + GluN2A During

After

Rel: Hearing Onset

C Response Magnitude

a lack of GluN2B along with high expression of GluN2A and C at mature synapses (Steinert et al., 2010). Maturation of NMDA-R responses contributes to increased fidelity of auditory synaptic transmission (Taschenberger and von Gersdorff, 2000; Futai et al., 2001; Joshi and Wang, 2002) and calcium influx through NMDA-Rs at mature VCN-MNTB synapses is implicated in the production of nitric oxide through activation of nitric oxide synthase (Steinert et al., 2008). Nitric oxide changes the excitability of MNTB neurons by reducing Kv3 potassium channel conductances, increasing action potential duration and decreasing firing rate, impacting the inhibitory outputs from the MNTB to LSO and MSO.

NMDA-REPSC Reduction (%)

J. T. Sanchez et al. / Neuroscience 285 (2015) 248–259

Developmental Regulation AMPA-R

NMDA-R

Before

During

After

Rel: Hearing Onset

Fig. 4. Developmental profile of NMDA-Rs in the lower auditory pathway. (A) Representative traces of NMDA-R-mediated EPSCs recorded in voltage clamp configuration from the avian NL (left panel). NMDA-R responses become faster with development relative to hearing onset (before hearing onset = blue trace, after hearing onset = red trace). NMDA-R responses in NL are more sensitive to GluN2B-specific antagonist before hearing onset (right panel). +2BBLOCK = application of Ro25-6981 (1 lM). (B) NMDA-Rs switch subunit content from predominately GluN2B-containing to predominately GluN2A-containing receptors in NL. This switch parallels developmental time points relative to before, during, and after hearing onset. (C) Developmental regulation of NMDA-R response magnitude as a function of hearing onset in the lower auditory pathway. AMPA-R response is shown as a gray line for comparison. Similar to AMPARs, NMDA-R response magnitude is upregulated and peaks during hearing onset. Unlike AMPA-Rs, which continue to increase in magnitude, NMDA-Rs are downregulated after hearing onset. Data in (A and B) are adapted from Sanchez et al. (2010). Data in (C) are adapted from Lu and Trussell (2007), Sanchez et al. (2010).

responses could act as a temporal filter by generating action potentials only when strong and appropriately timed inputs coincide, discarding other inputs that occur outside a coincidence window. This type of activitydependent synaptic specialization may serve as a selection process, assisting the establishment of appropriate connections between NM and NL and sculpting binaural specialization of mature NL synapses (Sanchez et al., 2012).

J. T. Sanchez et al. / Neuroscience 285 (2015) 248–259

Lateral lemniscus The mammalian dorsal nucleus of the lateral lemniscus (DNLL) receives substantial convergence of excitatory inputs from the MSO and LSO, and projects inhibitory outputs to the inferior colliculus (Oliver and Shneiderman, 1989; Huffman and Covey, 1995). NMDARs are located in the DNLL well into maturation and

contribute to dual-component excitatory responses (Wu and Kelly, 1996; Fu et al., 1997; Ammer et al., 2012). Early in development, the NMDA-R to AMPA-R response ratio is high. This ratio dramatically decreases with no change in the overall AMPA-R response, indicating a downregulation of NMDA-Rs with maturation (Ammer et al., 2012). In addition, NMDA-R response kinetics become faster and suggest changes in subunit composition. Despite NMDA-Rs downregulation, they have a functional role in the mature DNLL, where they integrate excitatory synaptic transmission from MSO and LSO

Spikes

A

Short-LatencyNEURONS PRE

20

0

AMPA-RBLOCK

0

PRE

NMDA-RBLOCK

200

Time (ms)

B

Spikes

Mammalian LSO. The mammalian LSO receives segregated inhibitory inputs from the MNTB and excitatory inputs from the VCN. The LSO uses these inputs to code intensity disparities between the two ears. At these synapses, NMDA-Rs play a developmental role in synaptic transmission and refinement (Noh et al., 2010). Immature inputs from the MNTB co-release the neurotransmitters c-aminobutyric acid (GABA) and glycine. Although inhibitory at mature synapses, these neurotransmitters are excitatory during early synaptic development (Kandler and Friauf, 1995; Awatramani et al., 2005), due to the well-established reversed concentration gradient of intracellular chloride during brain development (Cherubini et al., 1990; Kriegstein and Owens, 2001). Remarkably, these inputs from MNTB also release glutamate (Gillespie et al., 2005). Studies confirm synaptic colocalization of the vesicular transporter 3 with the vesicular GABA transporter (Boulland et al., 2004; Gillespie et al., 2005), indicating that excitatory and inhibitory neurotransmitters are co-released from a single MNTB terminal. The release of glutamate from inhibitory MNTB inputs allows compartmentalized calcium influx through NMDARs located on LSO dendrites (Kalmbach et al., 2010). These NMDA-R responses are prominent during a period of early synapse strengthening and are downregulated by hearing onset (Gillespie et al., 2005; Kalmbach et al., 2010). This indicates a specific window of synaptic refinement when inhibitory MNTB inputs are also excitatory. The depolarizing effects of immature GABA and glycine released at MNTB-LSO synapses – along with co-released glutamate – relieve magnesium blockade and activate NMDA-Rs (Gillespie et al., 2005). It has been hypothesized that these inhibitory synapses utilize well-established mechanisms of excitatory synaptic plasticity by modulating properties of GABA and glycine receptors, rather than traditional AMPA-R changes (Kandler and Gillespie, 2005). A similar window of developmental refinement exists at excitatory VCN-LSO synapses. These synapses are dominated by GluN2B-containing NMDA-Rs (Case and Gillespie, 2011; Case et al., 2011). Prior to hearing onset, a significant reduction in NMDA-R responses and a switch from GluN2B- to GluN2A-containing receptors occurs, coinciding with refinement observed at inhibitory MNTBLSO synapses (Kim and Kandler, 2003, 2010). During early development – when GluN2B subunits dominate – NMDA-Rs provide appropriate signaling for synaptic refinement (Case and Gillespie, 2011) Thus, synapsespecific activation of NMDA-Rs from both inhibitory and excitatory inputs is implicated in LSO refinement before hearing onset in mammals. Future research on NMDAR function after hearing onset is needed to elucidate their role in binaural hearing.

Long-LatencyNEURONS PRE

20

AMPA-RBLOCK

PRE

NMDA-RBLOCK

0 0

200

Time (ms)

C 100

AMPA-RBLOCK

NMDA-RBLOCK

Spike Reduction (%)

254

0

All Neurons

SLATENCY

LLATENCY

Fig. 5. NMDA-Rs contribute to temporal response patterns in the lower auditory pathway. (A) Post stimulus time histograms (PSTH) recorded from isolated single neurons with short first-spike latencies in the mammalian inferior colliculus. In vivo blockade of AMPA-Rs and NMDA-Rs differentially reduces the early and later components of sustained response patterns to a 100-ms tone, respectively. Tone duration represented by gray bar below the PSTHs. (B) PSTHs showing in vivo blockade of NMDA-Rs also have a strong effect on the reduction of action potentials throughout the entire temporal pattern of sustained responses, where as AMPA-R blockade has less effect. This result is dependent on the time occurrence of the first action potential following stimulus onset (long first-spike latency). (C) Contribution of AMPA-Rs and NMDA-Rs depends on first-spike latency in the inferior colliculus. The effects of drug application are plotted as mean spike reduction for all neurons sampled, including short- and long-latency neurons (SLATENCY and LLATENCY, respectively), regardless of their temporal response patterns. Both AMPA-R and NMDA-R blockade had major effects for all neurons, but NMDAR blockade was strongest for long-latency neurons. In (A and B), PRE = before drug application, AMPA-RBLOCK = NBQX application, NMDA-RBLOCK = CPP application. Data in (A) are adapted from Zhang and Trussell (1994a). Data in (B and C) are adapted from Zhang and Kelly (2001), Sanchez et al. (2007).

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inputs. This integration results in a persistent GABAergic inhibition to the inferior colliculus. Longer lasting NMDA-R conductances amplify postsynaptic responses more efficiently than AMPA-Rs due to summation of underlying NMDA-R responses (Porres et al., 2011; Ammer et al., 2012). NMDA-R-mediated amplification contributes to large amounts of GABAergic inhibition (Porres et al., 2011) and helps shape binaural response properties of inferior colliculus neurons important for signal discrimination (Kelly and Kidd, 2000; Burger and Pollak, 2001). Inferior colliculus The inferior colliculus integrates frequency and temporal information from lower brainstem structures. A downregulation – but not elimination – of NMDA-R responses occurs with maturation, (Ma et al., 2002) and studies from a variety of species reinforce the view that AMPA-Rs and NMDA-Rs mediate early and later elements of synaptic responses, respectively (Fig. 5A) (Faingold et al., 1989; Feldman and Knudsen, 1994; Zhang and Kelly, 2001; Ma et al., 2002; Wu et al., 2004). However, blocking AMPA-Rs does not always eliminate early responses as expected (Kelly and Zhang, 2002) and action potential generation can be mediated by NMDA-Rs independent of AMPA-R involvement (Fig. 5B) (Sivaramakrishnan and Oliver, 2006; Sanchez et al., 2007). A possible explanation for this may be the contribution of different NMDA-R subunits found in the inferior colliculus. Although the exact subunit composition is not known, significant levels of GluN2D-containing NMDA-Rs are abundant in the mature inferior colliculus (Wenzel et al., 1996). GluN2D-containing NMDA-Rs have a weaker voltage-dependent magnesium block of the channel (Kirson and Yaari, 1996) and may be associated with AMPA-R-independent NMDA-R activity. NMDA-Rs also have a strong influence on neurons with long first-spike action potential latencies. Longlatency responses occur tens of milliseconds after the onset of a stimulus and are required for matching the timing of sensory-evoked activity to appropriate behavioral responses (Casseday and Covey, 1996). Application of an NMDA-R antagonist significantly reduced action potential generation for neurons with long first-spike latencies (>10 ms) (Fig. 5C) (Sanchez et al., 2007). Previous hypotheses for the creation of longlatency responses include fast inhibition and variations in afferent input timing (Park and Pollak, 1993; Saitoh and Suga, 1995; Casseday and Covey, 1996) (Haplea et al., 1994; Klug et al., 2000). Neither however, accounts for extreme variability of first-spike latency – up to 50 ms – occurring in the inferior colliculus (Park and Pollak, 1993). Instead, a differential abundance and/or placement of subunit-specific NMDA-Rs could create a distribution of response timing (Sanchez et al., 2007, 2008). The slower time course and weaker magnesium sensitivity of independent, GluN2D-containing NMDA-R responses are appropriate features needed for the generation of long first-spike latencies, as reported in the visual system (Augustinaite and Heggelund, 2007). Thus, the

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generation of action potentials by NMDA-Rs in longlatency neurons provides a mechanism for coordinating timing variability of sensory inputs to the inferior colliculus. NMDA-Rs also play a role in mediating synaptic plasticity, as most neurons in the inferior colliculus exhibit synaptic enhancement that resembles LTP (Hosomi et al., 1995; Zhang and Wu, 2000; Wu et al., 2002). However, this synaptic enhancement is expressed through both AMPA-Rs and NMDA-Rs and, in a subset of neurons, the magnitude of synaptic enhancement was dependent on stimulus frequency as well as internal calcium levels. LTP was more prominent using higher tetanus stimulus frequencies and with internal calcium levels buffered, indicating synaptic strengthening was partially dependent on calcium influx through voltagegated calcium channels rather than NMDA-Rs (Wu et al., 2002). It is currently unknown how similar synaptic enhancement in the inferior colliculus is to LTP in the hippocampus, but it is tempting to speculate that it involves similar mechanisms induced by NMDA-R activity. Synaptic enhancement may provide a substrate for auditory learning (Wu et al., 2002) and NMDA-Rs have been implicated in this process (Feldman and Knudsen, 1998). For example, in the barn owl’s inferior colliculus, differences in arrival time of sound from two ears are mapped across frequency-specific channels. The output of these signals converges in the external nucleus of the inferior colliculus (ICX) and creates auditory space maps (Gold and Knudsen, 2000b). Information is then communicated to the auditory thalamus and optic tectum, where space-specific neurons have overlapping auditory and visual receptive fields, creating a multimodal pathway (Knudsen et al., 2000). Evidence of auditory learning is well documented in this pathway. Adaptive adjustments in localization abilities are learned by juvenile barn owls when auditory or visual inputs are deprived and traces of this early learning persist into adulthood (Knudsen, 1983; Knudsen and Mogdans, 1992; Mogdans and Knudsen, 1992; Gold and Knudsen, 1999, 2000a). Interestingly, studies show that blocking NMDA-Rs in the ICX inhibits the expression of learned responses (Feldman and Knudsen, 1998) and anatomical studies support a reorganization of the inferior colliculus to ICX projection that reflects changes in localization abilities (Feldman and Knudsen, 1997). Although LTP has not been tested directly in ICX, it is conceivable that during auditory learning synaptic properties are influenced by LTP-like processes dependent on NMDA-R activity. Synaptic enhancement and traces of auditory learning however were observed in young animals. In the case of LTP-like plasticity, responses were recorded around hearing onset (Wu et al., 2002). Thus, plastic-like changes in synaptic strength may be confounded with naturally occurring developmental events. Additional research is needed to confirm synaptic enhancement resembling long-term plasticity is present in mature animals and induction, maintenance, and expression of this process is NMDA-R dependent. Overall, NMDA-R function follows a traditional developmental trajectory in the inferior colliculus; responses are downregulated relative to AMPA-R but

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maintained at low levels into maturation. At mature synapses however, NMDA-R responses are unique in that they are able to generate action potentials independent of AMPA-Rs, a factor likely due to different NMDA-R subunit compositions and anatomical arrangement – a process indicated in the generation of long first-spike latencies. In addition, NMDA-Rs mediate synaptic plasticity resembling LTP/LTD, although this has not been thoroughly investigated in mature animals.

CONCLUSION NMDA-Rs’ subunit composition and broad biophysical characteristics contribute to diverse functions in the lower auditory pathway. At the mammalian IHC-SGN synapse, NMDA-Rs are not involved in glutamatergic transmission and at maturation do not contain the GluN2A subunit. Instead, they retain high expression levels of GluN2B, C and D subunits. This expression pattern at IHC-SGN synapses is thought to contribute to the regulation of surface AMPA-R expression and provides a neurotrophic role following acute insult, assisting in the restoration of SGN inputs. Following chronic damage, NMDA-Rs have a negative influence by mediating sustained levels of depolarization and subsequent calcium influx. These functions are thought to contribute to auditory diseases including noiseinduced hearing loss, neural presbycusis, and tinnitus via aberrant excitation of the auditory nerve. A traditional role of NMDA-Rs emerges in the auditory brainstem. Developmentally, they contribute to late and slow excitatory responses that peak around hearing onset and are downregulated thereafter, a process coinciding with changes in synaptic refinement. In the DCN and inferior colliculus, synaptic refinement is evident through NMDA-R-dependent LTP/LTD-like processes. At maturation, faster NMDA-R responses persist compared to their immature counterparts, likely due to changes in subunit composition from GluN2B to GluN2A. This observation however, is challenged at the avian endbulb of Held and mammalian IHC-SGN synapses. Regardless, NMDA-R downregulation – in conjunction with their faster time course – supports functions related to aspects of hearing specializations at mature synapses. Here, NMDA-R function improves auditory processing by increasing the probability of action potential generation, regulating first-spike latency, and promoting reliable action potential firing; attributes commonly associated with AMPA-Rs. In closing, NMDARs play a variety of necessary roles in the lower auditory pathway and serve as a molecular candidate for further investigation in abnormal auditory processing.

DISCLOSURES The authors report no disclosures. Acknowledgments—Northwestern University School of Communication supported preparation of this manuscript. The authors would like to thank the two anonymous reviewers, Michaela Ritz and Drs. Simone Otto and R. Michael Burger for providing insightful comments.

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(Accepted 16 November 2014) (Available online 25 November 2014)