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Animal communication sounds exhibit complex temporal structure because of the amplitude fluctuations that comprise the sound envelope. In human speech, envelope modulations drive synchronized activity in auditory cortex (AC), which correlates strongly with comprehension (Giraud and Poeppel, 2012; Peelle and Davis, 2012; Haegens and Zion Golumbic, 2018). Studies of envelope coding in single neurons, performed in nonhuman animals, have focused on periodic amplitude modulation (AM) stimuli and use response metrics that are not easy to juxtapose with data from humans. In this study, we sought to bridge these fields. Specifically, we looked directly at the temporal relationship between stimulus envelope and spiking, and we assessed whether the apparent diversity across neurons' AM responses contributes to the population representation of speech-like sound envelopes. We gathered responses from single neurons to vocoded speech stimuli and compared them to sinusoidal AM responses in auditory cortex (AC) of alert, freely moving Mongolian gerbils of both sexes. While AC neurons displayed heterogeneous tuning to AM rate, their temporal dynamics were stereotyped. Preferred response phases accumulated near the onsets of sinusoidal AM periods for slower rates (<8 Hz), and an over-representation of amplitude edges was apparent in population responses to both sinusoidal AM and vocoded speech envelopes. Crucially, this encoding bias imparted a decoding benefit: a classifier could discriminate vocoded speech stimuli using summed population activity, while higher frequency modulations required a more sophisticated decoder that tracked spiking responses from individual cells. Together, our results imply that the envelope structure relevant to parsing an acoustic stream could be read-out from a distributed, redundant population code. SIGNIFICANCE STATEMENT Animal communication sounds have rich temporal structure and are often produced in extended sequences, including the syllabic structure of human speech. Although the auditory cortex (AC) is known to play a crucial role in representing speech syllables, the contribution of individual neurons remains uncertain. Here, we characterized the representations of both simple, amplitude-modulated sounds and complex, speech-like stimuli within a broad population of cortical neurons, and we found an overrepresentation of amplitude edges. Thus, a phasic, redundant code in auditory cortex can provide a mechanistic explanation for segmenting acoustic streams like human speech., (Copyright © 2023 the authors.)

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory CNS. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABA A and GABA B receptor-mediated IPSPs in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes; but when administered after the critical period, it only restored GABA B receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABA A responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABA A and GABA B IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented. SIGNIFICANCE STATEMENT Even a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property., (Copyright © 2019 the authors.)

Skill learning is fundamental to the acquisition of many complex behaviors that emerge during development. For example, years of practice give rise to perceptual improvements that contribute to mature speech and language skills. While fully honed learning skills might be thought to offer an advantage during the juvenile period, the ability to learn actually continues to develop through childhood and adolescence, suggesting that the neural mechanisms that support skill learning are slow to mature. To address this issue, we asked whether the rate and magnitude of perceptual learning varies as a function of age as male and female gerbils trained on an auditory task. Adolescents displayed a slower rate of perceptual learning compared with their young and mature counterparts. We recorded auditory cortical neuron activity from a subset of adolescent and adult gerbils as they underwent perceptual training. While training enhanced the sensitivity of most adult units, the sensitivity of many adolescent units remained unchanged, or even declined across training days. Therefore, the average rate of cortical improvement was significantly slower in adolescents compared with adults. Both smaller differences between sound-evoked response magnitudes and greater trial-to-trial response fluctuations contributed to the poorer sensitivity of individual adolescent neurons. Together, these findings suggest that elevated sensory neural variability limits adolescent skill learning. SIGNIFICANCE STATEMENT The ability to learn new skills emerges gradually as children age. This prolonged development, often lasting well into adolescence, suggests that children, teens, and adults may rely on distinct neural strategies to improve their sensory and motor capabilities. Here, we found that practice-based improvement on a sound detection task is slower in adolescent gerbils than in younger or older animals. Neural recordings made during training revealed that practice enhanced the sound sensitivity of adult cortical neurons, but had a weaker effect in adolescents. This latter finding was partially explained by the fact that adolescent neural responses were more variable than in adults. Our results suggest that one mechanistic basis of adult-like skill learning is a reduction in neural response variability., (Copyright © 2019 the authors.)

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity., Significance Statement: The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds., (Copyright © 2016 the authors 0270-6474/16/3611097-10$15.00/0.)

Sensory pathways display heightened plasticity during development, yet the perceptual consequences of early experience are generally assessed in adulthood. This approach does not allow one to identify transient perceptual changes that may be linked to the central plasticity observed in juvenile animals. Here, we determined whether a brief period of bilateral auditory deprivation affects sound perception in developing and adult gerbils. Animals were reared with bilateral earplugs, either from postnatal day 11 (P11) to postnatal day 23 (P23) (a manipulation previously found to disrupt gerbil cortical properties), or from P23-P35. Fifteen days after earplug removal and restoration of normal thresholds, animals were tested on their ability to detect the presence of amplitude modulation (AM), a temporal cue that supports vocal communication. Animals reared with earplugs from P11-P23 displayed elevated AM detection thresholds, compared with age-matched controls. In contrast, an identical period of earplug rearing at a later age (P23-P35) did not impair auditory perception. Although the AM thresholds of earplug-reared juveniles improved during a week of repeated testing, a subset of juveniles continued to display a perceptual deficit. Furthermore, although the perceptual deficits induced by transient earplug rearing had resolved for most animals by adulthood, a subset of adults displayed impaired performance. Control experiments indicated that earplugging did not disrupt the integrity of the auditory periphery. Together, our results suggest that P11-P23 encompasses a critical period during which sensory deprivation disrupts central mechanisms that support auditory perceptual skills., Significance Statement: Sensory systems are particularly malleable during development. This heightened degree of plasticity is beneficial because it enables the acquisition of complex skills, such as music or language. However, this plasticity comes with a cost: nervous system development displays an increased vulnerability to the sensory environment. Here, we identify a precise developmental window during which mild hearing loss affects the maturation of an auditory perceptual cue that is known to support animal communication, including human speech. Furthermore, animals reared with transient hearing loss display deficits in perceptual learning. Our results suggest that speech and language delays associated with transient or permanent childhood hearing loss may be accounted for, in part, by deficits in central auditory processing mechanisms., (Copyright © 2015 the authors 0270-6474/15/3510831-12$15.00/0.)

Auditory learning is associated with an enhanced representation of acoustic cues in primary auditory cortex, and modulation of inhibitory strength is causally involved in learning. If this inhibitory plasticity is associated with task learning and improvement, its expression should emerge and persist until task proficiency is achieved. We tested this idea by measuring changes to cortical inhibitory synaptic transmission as adult gerbils progressed through the process of associative learning and perceptual improvement. Using either of two procedures, aversive or appetitive conditioning, animals were trained to detect amplitude-modulated noise and then tested daily. Following each training session, a thalamocortical brain slice was generated, and inhibitory synaptic properties were recorded from layer 2/3 pyramidal neurons. Initial associative learning was accompanied by a profound reduction in the amplitude of spontaneous IPSCs (sIPSCs). However, sIPSC amplitude returned to control levels when animals reached asymptotic behavioral performance. In contrast, paired-pulse ratios decreased in trained animals as well as in control animals that experienced unpaired conditioned and unconditioned stimuli. This latter observation suggests that inhibitory release properties are modified during behavioral conditioning, even when an association between the sound and reinforcement cannot occur. These results suggest that associative learning is accompanied by a reduction of postsynaptic inhibitory strength that persists for several days during learning and perceptual improvement., (Copyright © 2015 the authors 0270-6474/15/356318-08$15.00/0.)

Animals often listen selectively for particular sounds, a strategy that could alter neural encoding mechanisms to maximize the ability to detect the target. Here, we recorded auditory cortex neuron responses in well trained, freely moving gerbils as they performed a tone detection task. Each trial was initiated by the animal, providing a predictable time window during which to listen. No sound was presented on nogo trials, permitting us to assess spontaneous activity on trials in which a signal could have been expected, but was not delivered. Immediately after animals initiated a trial, auditory cortex neurons displayed a 26% reduction in spontaneous activity. Moreover, when stimulus-driven discharge rate was referenced to this reduced baseline, a larger fraction of auditory cortex neurons displayed a detection threshold within 10 dB of the behavioral threshold. These findings suggest that auditory cortex spontaneous discharge rate can be modulated transiently during task performance, thereby increasing the signal-to-noise ratio and enhancing signal detection.

Manipulations of the sensory environment typically induce greater changes to the developing nervous system than they do in adulthood. The relevance of these neural changes can be evaluated by examining the age-dependent effects of sensory experience on quantitative measures of perception. Here, we measured frequency modulation (FM) detection thresholds in adult gerbils and investigated whether diminished auditory experience during development or in adulthood influenced perceptual performance. Bilateral conductive hearing loss (CHL) of ≈30 dB was induced either at postnatal day 10 or after sexual maturation. All animals were then trained as adults to detect a 5 Hz FM embedded in a continuous 4 kHz tone. FM detection thresholds were defined as the minimum deviation from the carrier frequency that the animal could reliably detect. Normal-hearing animals displayed FM thresholds of 25 Hz. Inducing CHL, either in juvenile or adult animals, led to a deficit in FM detection. However, this deficit was greater for juvenile onset hearing loss (89 Hz) relative to adult onset hearing loss (64 Hz). The effects could not be attributed to sensation level, nor were they correlated with proxies for attention. The thresholds displayed by CHL animals were correlated with shallower psychometric function slopes, suggesting that hearing loss was associated with greater variance of the decision variable, consistent with increased internal noise. The results show that decreased auditory experience has a greater impact on perceptual skills when initiated at an early age and raises the possibility that altered development of CNS synapses may play a causative role.

Sensory experience during development can modify the CNS and alter adult perceptual skills. While this principle draws support from deprivation or chronic stimulus exposure studies, the effect of training is addressed only in adults. Here, we asked whether a brief period of training during development can exert a unique impact on adult perceptual skills. Juvenile gerbils were trained to detect amplitude modulation (AM), a stimulus feature elemental to animal communication sounds. When the performance of these juvenile-trained animals was subsequently assessed in adulthood, it was superior to a control group that received an identical regimen of training as adults. The juvenile-trained animals displayed significantly better AM detection thresholds. This was not observed in an adult group that received only exposure to AM stimuli as juveniles. To determine whether enhanced adult performance was due solely to learning the conditioned avoidance procedure, juveniles were trained on frequency modulation (FM) detection, and subsequently assessed on AM detection as adults. These animals displayed significantly poorer AM detection thresholds than all other groups. Thus, training on a specific auditory task (AM detection) during development provided a benefit to performance on that task in adulthood, whereas an identical training regimen in adulthood did not bring about this enhancement. In contrast, there was a cost, in adulthood, following developmental training on a different task (FM detection). Together, the results demonstrate a period of heightened sensitivity in the developing CNS such that behavioral training in juveniles has a unique impact on adult behavioral capabilities.

During development, detection for many percepts matures gradually. This provides a natural system in which to investigate the neural mechanisms underlying performance differences: those aspects of neural activity that mature in conjunction with behavioral performance are more likely to subserve detection. In principle, the limitations on performance could be attributable to either immature sensory encoding mechanisms or an immature decoding of an already-mature sensory representation. To evaluate these alternatives in awake gerbil auditory cortex, we measured neural detection of sinusoidally amplitude-modulated (sAM) stimuli, for which behavioral detection thresholds display a prolonged maturation. A comparison of single-unit responses in juveniles and adults revealed that encoding of static tones was adult like in juveniles, but responses to sAM depth were immature. Since perceptual performance may reflect the activity of an animal's most sensitive neurons, we analyzed the d prime curves of single neurons and found an equivalent percentage with highly sensitive thresholds in juvenile and adult animals. In contrast, perceptual performance may reflect the pooling of information from neurons with a range of sensitivities. We evaluated a pooling model that assumes convergence of a population of inputs at a downstream target neuron and found poorer sAM detection thresholds for juveniles. Thus, if sAM detection is based on the most sensitive neurons, then immature behavioral performance is best explained by an immature decoding mechanism. However, if sAM detection is based on a population response, then immature detection thresholds are more likely caused by an inadequate sensory representation.

Short-term changes in synaptic gain support information processing throughout the CNS, yet we know little about the developmental regulation of such plasticity. Here we report that auditory experience is necessary for the normal maturation of synaptic inhibitory short-term plasticity (iSTP) in the auditory cortex, and that presynaptic GABA(B) receptors regulate this development. Moderate or severe hearing loss was induced in gerbils, and iSTP was characterized by measuring inhibitory synaptic current amplitudes in response to repetitive stimuli. We reveal a profound developmental shift of iSTP from depressing to facilitating after the onset of hearing. Even moderate hearing loss prevented this shift. This iSTP change was mediated by a specific class of inhibitory interneurons, the low-threshold spiking cells. Further, using paired recordings, we reveal that presynaptic GABA(B) receptors at interneuron-pyramidal connections regulate iSTP in an experience-dependent manner. This novel synaptic mechanism may support the emergence of mature temporal processing in the auditory cortex.

Long-term synaptic plasticity is a putative mechanism for learning in adults. However, there is little understanding of how synaptic plasticity mechanisms develop or whether their maturation depends on experience. Since inhibitory synapses are particularly malleable to sensory stimulation, long-lasting potentiation of inhibitory synapses was characterized in auditory thalamocortical slices. Intracortical high-frequency electrical stimulation led to a 67% increase in inhibitory synaptic currents. In the absence of stimulation, inhibitory potentiation was induced by a brief exposure to exogenous brain-derived neurotrophic factor (BDNF). BDNF exposure occluded any additional potentiation by high-frequency afferent stimulation, suggesting that BDNF signaling is sufficient to account for inhibitory potentiation. Moreover, inhibitory potentiation was reduced significantly by extracellular application of a BDNF scavenger or by intracellular blockade of BDNF receptor [tropomyosin-related kinase B (TrkB)] signaling. In contrast, glutamatergic or GABAergic antagonists did not prevent the induction of inhibitory potentiation. Since BDNF and TrkB expression are influenced strongly by activity, we predicted that inhibitory potentiation would be diminished by manipulations that decrease central auditory activity, such as hearing loss. Two forms of hearing loss were examined: conductive hearing loss in which the cochleae are not damaged or sensorineural hearing loss in which both cochleae are removed. Both forms of hearing loss were found to reduce significantly the magnitude of inhibitory potentiation. These data indicate that early experience is necessary for the normal development of BDNF-mediated long-lasting inhibitory potentiation, which may be associated with perceptual deficits at later ages.

Although sensorineural hearing loss (SNHL) is known to compromise central auditory structure and function, the impact of milder forms of hearing loss on cellular neurophysiology remains mostly undefined. We induced conductive hearing loss (CHL) in developing gerbils, reared the animals for 8-13 d, and subsequently assessed the temporal features of auditory cortex layer 2/3 pyramidal neurons in a thalamocortical brain slice preparation with whole-cell recordings. Repetitive stimulation of the ventral medial geniculate nucleus (MGv) evoked robust short-term depression of the postsynaptic potentials in control neurons, and this depression increased monotonically at higher stimulation frequencies. In contrast, CHL neurons displayed a faster rate of synaptic depression and a smaller asymptotic amplitude. Moreover, the latency of MGv evoked potentials was consistently longer in CHL neurons for all stimulus rates. A separate assessment of spike frequency adaptation in response to trains of injected current pulses revealed that CHL neurons displayed less adaptation compared with controls, although there was an increase in temporal jitter. For each of these properties, nearly identical findings were observed for SNHL neurons. Together, these data show that CHL significantly alters the temporal properties of auditory cortex synapses and spikes, and this may contribute to processing deficits that attend mild to moderate hearing loss.

The neural representation of meaningful stimulus features is thought to rely on precise discharge characteristics of the auditory cortex. Precisely timed onset spikes putatively carry the majority of stimulus-related information in auditory cortical neurons but make a small contribution to stimulus representation in the auditory midbrain. Because these conclusions derive primarily from anesthetized preparations, we reexamined temporal coding properties of single neurons in the awake gerbil inferior colliculus (IC) and compared them with primary auditory cortex (AI). Surprisingly, AI neurons displayed a reduction of temporal precision compared with those in the IC. Furthermore, this hierarchical transition from high to low temporal fidelity was observed for both static and dynamic stimuli. Because most of the data that support temporal precision were obtained under anesthesia, we also reexamined response properties of IC and AI neurons under these conditions. Our results show that anesthesia has profound effects on the trial-to-trial variability and reliability of discharge and significantly improves the temporal precision of AI neurons to both tones and amplitude-modulated stimuli. In contrast, IC temporal properties are only mildly affected by anesthesia. These results underscore the pitfalls of using anesthetized preparations to study temporal coding. Our findings in awake animals reveal that AI neurons combine faster adaptation kinetics and a longer temporal window than evident in IC to represent ongoing acoustic stimuli.

Developmental hearing impairments compromise sound discrimination, speech acquisition, and cognitive function; however, the adjustments of functional properties in the primary auditory cortex (A1) remain unknown. We induced sensorineural hearing loss (SNHL) in developing gerbils and then reared the animals for several days. The intrinsic membrane and synaptic properties of layer 2/3 pyramidal neurons were subsequently examined in a thalamocortical brain slice preparation with whole-cell recordings and electron microscopic immunocytochemistry. SNHL neurons displayed a depolarized resting membrane potential, an increased input resistance, and a higher incidence of sustained firing. They also exhibited significantly larger thalamocortically and intracortically evoked excitatory synaptic responses, including a greater susceptibility to the NMDA receptor antagonist AP-5 and the NR2B subunit antagonist ifenprodil. This correlated with an increase in NR2B labeling of asymmetric synapses, as visualized ultrastructurally. Furthermore, decreased frequency and increased amplitude of miniature EPSCs (mEPSCs) in SNHL neurons suggest that a decline in presynaptic release properties is compensated by an increased excitatory response. To verify that the increased thalamocortical excitation was elicited by putative monosynaptic connections, minimum amplitude ventral medial geniculate nucleus-evoked EPSCs were recorded. These minimum-evoked responses were of larger amplitude, and the NMDAergic currents were also larger and longer in SNHL neurons. These findings were supported by significantly longer AP-5-sensitive durations and larger amplitudes of mEPSCs. Last, the amplitudes of intracortically evoked monosynaptic and polysynaptic GABAergic inhibitory synaptic responses were significantly smaller in SNHL neurons. These alterations in cellular properties after deafness reflect an attempt by A1 to sustain an operative level of cortical excitability that may involve homeostatic mechanisms.

Loss of sensory function leads to atrophy or death within the developing CNS, yet little is known about the physiology of remaining synapses. After bilateral deafening, gramicidin-perforated-patch recordings were obtained from gerbil inferior colliculus neurons in a brain slice preparation. Afferent-evoked IPSPs had a diminished ability to block current-evoked action potentials in deafened neurons. This change could be attributed, in part, to a loss of potassium-dependent chloride transport function, with little change in K-Cl cotransporter expression. Treatments that suppressed chloride cotransport (bumetanide, cesium, and genistein) had little or no effect on neurons from deafened animals. These same treatments depolarized the E(IPSC) of control neurons. Semiquantitative RT-PCR and immunohistochemical staining indicated no change in the expression of chloride cotransporter mRNA or protein after deafness. Therefore, profound hearing loss leads rapidly to the disruption of chloride homeostasis, which is likely attributable to the dysfunction of the potassium-dependent chloride cotransport mechanism, rather than a downregulation of its expression. This results in inhibitory synapses that are less able to block excitatory events.

Neurons possess multiple voltage-dependent conductances specific for their function. To investigate how low-threshold outward currents improve the detection of small signals in a noisy background, we recorded from gerbil medial superior olivary (MSO) neurons in vitro. MSO neurons responded phasically, with a single spike to a step current injection. When bathed in dendrotoxin (DTX), most cells switched to tonic firing, suggesting that low-threshold potassium currents (I(KLT)) participated in shaping these phasic responses. Neurons were stimulated with a computer-generated steady barrage of random inputs, mimicking weak synaptic conductance transients (the "noise"), together with a larger but still subthreshold postsynaptic conductance, EPSG (the "signal"). DTX reduced the signal-to-noise ratio (SNR), defined as the ratio of probability to fire in response to the EPSG and the probability to fire spontaneously in response to noise. The reduction was mainly attributable to the increase of spontaneous firing in DTX. The spike-triggered reverse correlation indicated that, for spike generation, the neuron with I(KLT) required faster inward current transients. This narrow temporal integration window contributed to superior phase locking of firing to periodic stimuli before application of DTX. A computer model including Hodgkin-Huxley type conductances for spike generation and for I(KLT) (Rathouz and Trussell, 1998) showed similar response statistics. The dynamic low-threshold outward current increased SNR and the temporal precision of integration of weak subthreshold signals in auditory neurons by suppressing false positives.

The developmental refinement of excitatory synapses is often influenced by neuronal activity, and underlying synaptic mechanisms have been suggested. In contrast, few studies have asked whether inhibitory synapses are reorganized during development and whether this is accompanied by use-dependent changes of inhibitory synaptic strength. The topographic inhibitory projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) undergoes synapse elimination during development (Sanes and Takács, 1993). To determine whether there is an associated period of synaptic plasticity, whole-cell recordings were obtained from developing LSO neurons of gerbils in a brain slice preparation. In current-clamp recordings, low-frequency stimulation of the MNTB led to a decline in IPSP amplitude by 43%. In voltage-clamp recordings, hyperpolarized LSO neurons also exhibited a long-lasting depression of MNTB-evoked inhibitory synaptic currents (34%) after low-frequency stimulation. When LSO neurons were depolarized, low-frequency stimulation of the MNTB produced a significantly larger inhibitory synaptic depression (59%). This synaptic plasticity declined dramatically by postnatal days 17-19. Similar to well studied forms of excitatory synaptic plasticity, inhibitory depression depended on postsynaptic calcium. We propose that such activity-dependent synaptic depression may support the developmental rearrangement of inhibitory terminals as they compete with neighboring excitatory and/or inhibitory inputs.

To determine whether afferent innervation regulates the strength of inhibitory connections in the gerbil auditory midbrain, both cochleas were surgically removed in postnatal day 7 animals, before sound-driven activity is first observed. Inhibitory synaptic currents were measured in a brain slice preparation 1-7 d after the ablations. Whole-cell and gramicidin-perforated patch recordings were obtained from inferior colliculus neurons, and IPSCs were evoked by stimulation of the commissure of the inferior colliculus (CIC) or the ipsilateral lateral lemniscus (LL) in the presence of kynurenic acid. Deafferentation led to a 24 mV depolarizing shift in the IPSC equilibrium potential within 1 d of deafferentation. As a consequence, there was a large reduction of IPSC amplitude at a holding potential of -20 mV in neurons from bilaterally ablated animals. Furthermore, both afferent pathways displayed a 50% reduction of the inhibitory synaptic conductance after deafferentation, indicating that driving force was not solely responsible for the decline in IPSC amplitude. When paired pulses were delivered to the LL or CIC pathway in control neurons, the evoked IPSCs exhibited facilitation. However, paired pulse facilitation was nearly eliminated after deafferentation. Thus, normal innervation affects inhibitory synaptic strength by regulating postsynaptic chloride homeostasis and presynaptic transmitter release properties.

GABAergic and glycinergic circuits are found throughout the auditory brainstem, and it is generally assumed that transmitter phenotype is established early in development. The present study documents a profound transition from GABAergic to glycinergic transmission in the gerbil lateral superior olive (LSO) during the first 2 postnatal weeks. Whole-cell voltage-clamp recordings were obtained from LSO neurons in a brain slice preparation, and IPSCs were evoked by electrical stimulation of the medial nucleus of the trapezoid body (MNTB), a known glycinergic projection in adult animals. GABAergic and glycinergic components were identified by blocking transmission with bicuculline and strychnine (SN), respectively. In the medial limb of LSO, there was a dramatic change in the GABAergic IPSC component, decreasing from 78% at postnatal day 3 (P3)-P5 to 12% at P12-P16. There was an equal and opposite increase in the glycinergic component during this same period. Direct application of GABA also elicited significantly larger amplitude and longer duration responses in P3-P5 neurons compared with glycine-evoked responses. In contrast, MNTB-evoked IPSCs in lateral limb neurons were more sensitive to SN throughout development. Consistent with the electrophysiological observations, there was a reduction in staining for the beta2,3-GABAA receptor subunit from P4 to P14, whereas staining for the glycine receptor-associated protein gephyrin increased. Brief exposure to baclofen depressed transmission at excitatory and inhibitory synapses for approximately 15 min, suggesting a GABAB-mediated metabotropic signal. Collectively, these data demonstrate a striking switch from GABAergic to glycinergic transmission during postnatal development. Although GABA and glycine elicit similar postsynaptic ionotropic responses, our results raise the possibility that GABAergic transmission in neonates may play a developmental role distinct from that of glycine.

We have recently discovered a paradoxical aftereffect associated with inhibition in the gerbil auditory midbrain. Single neurons in the inferior colliculus (IC) were assessed for sensitivity to a virtual motion stimulus produced by modulating the interaural level difference (ILD), a major cue for sound localization. The class of neuron studied was predominantly excited by contralateral stimulation and inhibited by ipsilateral stimulation. Sound pressure level was modulated trapezoidally at the ipsilateral "inhibitory" ear, whereas the contralateral "excitatory" level remained constant. When the inhibitory stimulus was decreased within a range of sound levels that maintained suppression under static conditions, an unexpected discharge was often elicited, apparently because of an aftereffect of synaptic inhibition. In contrast, when the inhibitory stimulus was increased within a range of sound levels that produced only modest suppression under static conditions, neuronal discharge was often profoundly suppressed. In many cases the "conditioned enhancement" or "conditioned suppression" persisted for several seconds after the modulation of ILD, and such conditioned responses were influenced by the modulation depth and rate. To test the effect of inhibition in the IC directly, glycine and GABA were pulsed from a glass recording pipette during a constant monaural excitatory stimulus. The acoustically elicited discharge rate was potentiated markedly if preceded immediately by the brief (0.5-10 sec) application of inhibitory transmitter. Collectively, these results revealed unusually long-lasting effects of inhibition that may establish a new range of acoustic cues to which the neuron responds best. This may have broad implications for processing ensuing auditory stimuli.