LFP publications

Introduction Sensory processing depends on interactions between neural circuits that convey and regulate information across cortical and subcortical networks. Classical frameworks distinguish driving inputs, which transmit sensory content via suprathreshold activation, from modulatory inputs, which alter neuronal excitability without directly eliciting spiking. However, physiological signatures of these circuit types that generalize widely across distributed brain regions remain unclear. Methods We functionally differentiated driving and modulatory circuits in the awake macaque brain by jointly quantifying suprathreshold multiunit activity (MUA) and oscillatory phase coherence (inter-trial coherence, ITC) across eight cortical and thalamic structures during auditory, visual, and eye-movement conditions. Results Preferred sensory stimuli elicited broadband ITC increases accompanied by robust MUA, yielding relatively uniform spectral distributions across adjacent frequency bands, consistent with driving inputs. In contrast, non-preferred sensory and eye-movement related events produced narrowband, frequency-specific ITC modulation without concurrent firing, characterized by dominant peaks at stimulation or event rates, consistent with modulatory inputs. These two response types were observed within individual regions, revealing two separable modes of neural activity. Discussion This narrowband ITC modulation is indicative of coordinated phase alignment, capable of dynamically regulating information transfer mediated by driving inputs across thalamocortical circuits. These findings identify distinct spectrotemporal signatures of driving and modulatory circuit properties across cortical and thalamic levels and demonstrate that subthreshold oscillatory modulation is a widespread phenomenon reflecting cross-modal and saccadic-related influences on neural excitability.

We describe properties and laminar organization of visual and auditory responses sampled with linear electrode arrays in and around the supplementary eye field of four macaque monkeys performing a visually guided task with a tone secondary reinforcer. Of pyramidal neurons in all layers and interneurons in L3 and L5/6, one-quarter were visually responsive, one-quarter, auditory, with 30% bimodal. Visual neurons were less common rostral, lateral, and medial to the supplementary eye field. Facilitated visual and auditory responses were much more common than suppressed. Pyramidal and interneurons responded to the stimulus in either hemifield with a weak bias for contralateral targets. Visual response latencies were comparable to values previously reported and later than auditory responses. Facilitated visual responses of interneurons preceded those of pyramidal neurons. Transient visual responses preceded sustained. Current-source density revealed visually evoked current sinks after auditory sinks that were transient for bright flashes and prolonged for the discrete task target. The earliest sink appeared at the L3 to L5 border and spread superficially and deeper with idiosyncratic variability across monkeys. These findings reveal new details about sensory processing in medial frontal cortex and complement our previous descriptions of the functional properties and laminar organization of neurons supporting cognitive control.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms observed in psychiatric diseases. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple aspects of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. We observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by gamma frequency stimulation of PVNs. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap‐induced prepulse inhibition (gap‐PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap‐PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise‐exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise‐induced hearing loss. Our results suggest that chronic “nondestructive” noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

Animacy perception, the ability to discern living from non-living entities, is crucial for survival and social interaction, as it includes recognizing abstract concepts such as movement, purpose, and intentions. This process involves interpreting cues that may suggest the intentions or actions of others. It engages the temporal cortex (TC), particularly the superior temporal sulcus (STS) and the adjacent region of the inferior temporal cortex (ITC), as well as the dorsomedial prefrontal cortex (dmPFC). However, it remains unclear how animacy is dynamically encoded over time in these brain areas and whether its processing is distributed or localized. In this study, we addressed these questions by employing a symbolic categorization task involving animate and inanimate objects using natural movie stimuli. Simultaneously, electrocorticography were conducted in both the TC and dmPFC. Time-frequency analysis revealed region-specific frequency representations throughout the observation of the movies. Spatial searchlight decoding analysis demonstrated that animacy processing is represented in a distributed manner. Regions encoding animacy information were found to be dispersed across the fundus and lip of the STS, as well as in the ITC. Next, we examined whether these dispersed regions form functional networks. Independent component analysis revealed that the spatial distribution of the component with the most significant animacy information corresponded with the dispersed regions identified by the spatial decoding analysis. Furthermore, Granger causality analysis indicated that these regions exhibit frequency-specific directional functional connectivity, with a general trend of causal influence from the ITC to STS across multiple frequency bands. Notably, a prominent feedback flow in the alpha band from the ITC to both the ventral bank and fundus of the STS was identified. These findings suggest a distributed and functionally interconnected neural substrate for animacy processing across the STS and ITC.

Background: Regional changes in corticostriatal transmission induced by phasic dopaminergic signals are an essential feature of the neural network responsible for instrumental reinforcement during discovery of an action. However, the timing of signals that are thought to contribute to the induction of corticostriatal plasticity is difficult to reconcile within the framework of behavioural reinforcement learning, because the reinforcer is normally delayed relative to the selection and execution of causally-related actions. Objective: While recent studies have started to address the relevance of delayed reinforcement signals and their impact on corticostriatal processing, our objective was to establish a model in which a sensory reinforcer triggers appropriately delayed reinforcement signals relayed to the striatum via intact neuronal pathways and to investigate the effects on corticostriatal plasticity. Methods: We measured corticostriatal plasticity with electrophysiological recordings using a light flash as a natural sensory reinforcer, and pharmacological manipulations were applied in an in vivo anesthetized rat model preparation. Results: We demonstrate that the spiking of striatal neurons evoked by single-pulse stimulation of the motor cortex can be potentiated by a natural sensory reinforcer, operating through intact afferent pathways, with signal timing approximating that required for behavioural reinforcement. The pharmacological blockade of dopamine receptors attenuated the observed potentiation of corticostriatal neurotransmission. Conclusion: This novel in vivo model of corticostriatal plasticity offers a behaviourally relevant framework to address the physiological, anatomical, cellular, and molecular bases of instrumental reinforcement learning.

Homeostatic plasticity, the ability of neurons to maintain their averaged activity constant around a set point value, is thought to account for the central hyperactivity after hearing loss. Here, we investigated the putative role of GABAergic neurotransmission in this mechanism after a noise-induced hearing loss larger than 50 dB in high frequencies in guinea pigs. The effect of GABAergic inhibition is linked to the normal functioning of K + –Cl– co-transporter isoform 2 (KCC2) which maintains a low intracellular concentration of chloride. The expression of membrane KCC2 were investigated before and after noise trauma in the ventral and dorsal cochlear nucleus (VCN and DCN, respectively) and in the inferior colliculus (IC). Moreover, the effect of gabazine (GBZ), a GABA antagonist, was also studied on the neural activity in IC. We show that KCC2 is downregulated in VCN, DCN and IC 3 days after noise trauma, and in DCN and IC 30 days after the trauma. As expected, GBZ application in the IC of control animals resulted in an increase of spontaneous and stimulus-evoked activity. In the noise exposed animals, on the other hand, GBZ application decreased the stimulus-evoked activity in IC neurons. The functional implications of these central changes are discussed.

Advancements in brain–machine interfaces and neurological treatments urgently require the development of improved brain electrodes applied for long-term implantation, where traditional and polymer options face challenges like size, tissue damage, and signal quality. Carbon nanotubes are emerging as a promising alternative, combining excellent electronic properties and biocompatibility, which ensure better neuron coupling and stable signal acquisition. In this study, a new flexible brain electrode array based on 99.99% purity of single-walled carbon nanotubes (SWCNTs) was developed, which has 30 um × 40 um size, about 5.1 kΩ impedance, and 14.01 dB signal-to-noise ratio (SNR). The long-term implantation experiment in vivo in mice shows the proposed brain electrode can maintain stable LFP signal acquisition over 12 weeks while still achieving an SNR of 3.52 dB. The histological analysis results show that SWCNT-based brain electrodes induced minimal tissue damage and showed significantly reduced glial cell responses compared to platinum wire electrodes. Long-term stability comes from SWCNT’s biocompatibility and chemical inertness, the electrode’s flexible and fine structure. Furthermore, the new brain electrode array can function effectively during 7-Tesla magnetic resonance imaging, enabling the collection of local field potential and even epileptic discharges during the magnetic scan. This study provides a comprehensive study of carbon nanotubes as invasive brain electrodes, providing a new path to address the challenge of long-term brain electrode implantation.

Background Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. Objectives Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. Methods Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. Results We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. Conclusions Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

The auditory steady-state response (ASSR) is a cortical oscillation induced by trains of 40 Hz acoustic stimuli. While the ASSR has been widely used in clinic measurement, the underlying neural mechanism remains poorly understood. In this study, we investigated the contribution of different stages of auditory thalamocortical pathwaymedial geniculate body (MGB), thalamic reticular nucleus (TRN), and auditory cortex (AC)to the generation and regulation of 40 Hz ASSR in C57BL/6 mice of both sexes. We found that the neural response synchronizing to 40 Hz sound stimuli was most prominent in the GABAergic neurons in the granular layer of AC and the ventral division of MGB (MGBv), which were regulated by optogenetic manipulation of TRN neurons. Behavioral experiments confirmed that disrupting TRN activity has a detrimental effect on the ability of mice to discriminate 40 Hz sounds. These findings revealed a thalamocortical mechanism helpful to interpret the results of clinical ASSR examinations. Significance Statement Our study contributes to clarifying the thalamocortical mechanisms underlying the generation and regulation of the auditory steady-state response (ASSR), which is commonly used in both clinical and neuroscience research to assess the integrity of auditory function. Combining a series of electrophysiological and optogenetic experiments, we demonstrate that the generation of cortical ASSR is dependent on the lemniscal thalamocortical projections originating from the ventral division of medial geniculate body to the GABAergic interneurons in the granule layer of the auditory cortex. Furthermore, the thalamocortical process for ASSR is strictly regulated by the activity of thalamic reticular nucleus (TRN) neurons. Behavioral experiments confirmed that dysfunction of TRN would cause a disruption of mice's behavioral performance in the auditory discrimination task.

In a natural acoustic environment, a preceding sound can suppress the perception of a succeeding sound which can lead to auditory phenomena such as forward masking and the precedence effect. The degree of suppression is dependent on the relationship between the sounds in sound quality, timing, and location. Correlates of such phenomena exist in sound-elicited activities of neurons in hearing-related brain structures. The present study recorded responses to pairs of leading-trailing sounds from ensembles of neurons in the rat’s inferior colliculus. Results indicated that a leading sound produced a suppressive aftereffect on the response to a trailing sound when the two sounds were colocalized at the ear contralateral to the site of recording (i.e., the ear that drives excitatory inputs to the inferior colliculus). The degree of suppression was reduced when the time gap between the two sounds was increased or when the leading sound was relocated to an azimuth at or close to the ipsilateral ear. Local blockage of the type-A γ-aminobutyric acid receptor partially reduced the suppressive aftereffect when a leading sound was at the contralateral ear but not at the ipsilateral ear. Local blockage of the glycine receptor partially reduced the suppressive aftereffect regardless of the location of the leading sound. Results suggest that a sound-elicited suppressive aftereffect in the inferior colliculus is partly dependent on local interaction between excitatory and inhibitory inputs which likely involves those from brainstem structures such as the superior paraolivary nucleus. These results are important for understanding neural mechanisms underlying hearing in a multiple-sound environment.

Fear extinction is a form of inhibitory learning that suppresses the expression of aversive memories and plays a key role in the recovery of anxiety and trauma-related disorders. Here, using male mice, we identify a cerebello-thalamo-cortical pathway regulating fear extinction. The cerebellar fastigial nucleus (FN) projects to the lateral subregion of the mediodorsal thalamic nucleus (MD), which is reciprocally connected with the dorsomedial prefrontal cortex (dmPFC). The inhibition of FN inputs to MD in male mice impairs fear extinction in animals with high fear responses and increases the bursting of MD neurons, a firing pattern known to prevent extinction learning. Indeed, this MD bursting is followed by high levels of the dmPFC 4 Hz oscillations causally associated with fear responses during fear extinction, and the inhibition of FN-MD neurons increases the coherence of MD bursts and oscillations with dmPFC 4 Hz oscillations. Overall, these findings reveal a regulation of fear-related thalamo-cortical dynamics by the cerebellum and its contribution to fear extinction.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), which consistently improves limb motor functions, shows mixed effects on speech functions in Parkinson’s disease (PD). One possible explanation for this discrepancy is that STN neurons may differentially encode speech and limb movement. However, this hypothesis has not yet been tested. We examined how STN is modulated by limb movement and speech by recording 69 single- and multi-unit neuronal clusters in 12 intraoperative PD patients. Our findings indicated: (1) diverse patterns of modulation in neuronal firing rates in STN for speech and limb movement; (2) a higher number of STN neurons were modulated by speech vs. limb movement; (3) an overall increase in neuronal firing rates for speech vs. limb movement; and (4) participants with longer disease duration had higher firing rates. These data provide new insights into the role of STN neurons in speech and limb movement.

Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persist in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret is identified as analogous to Type 2 theta that has been observed in rodents due to its sensitivity to atropine, and is modulated by behavioural state with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.

Anxiety is characteristic comorbidity of noise-induced hearing loss (NIHL), which causes physiological changes within the dentate gyrus (DG), a subfield of the hippocampus that modulates anxiety. However, which DG circuit underlies hearing loss-induced anxiety remains unknown. We utilize an NIHL mouse model to investigate short- and long-term synaptic plasticity in DG networks. The recently discovered longitudinal DG-DG network is a collateral of DG neurons synaptically connected with neighboring DG neurons and displays robust synaptic efficacy and plasticity. Furthermore, animals with NIHL demonstrate increased anxiety-like behaviors similar to a response to chronic restraint stress. These behaviors are concurrent with enhanced synaptic responsiveness and suppressed short- and long-term synaptic plasticity in the longitudinal DG-DG network but not in the transverse DG-CA3 connection. These findings suggest that DG-related anxiety is typified by synaptic alteration in the longitudinal DG-DG network.

In almost every natural environment, sounds are reflected by nearby objects, producing many delayed and distorted copies of the original sound, known as reverberation. Our brains usually cope well with reverberation, allowing us to recognize sound sources regardless of their environments. In contrast, reverberation can cause severe difficulties for speech recognition algorithms and hearing-impaired people. The present study examines how the auditory system copes with reverberation. We trained a linear model to recover a rich set of natural, anechoic sounds from their simulated reverberant counterparts. The model neurons achieved this by extending the inhibitory component of their receptive filters for more reverberant spaces, and did so in a frequency-dependent manner. These predicted effects were observed in the responses of auditory cortical neurons of ferrets in the same simulated reverberant environments. Together, these results suggest that auditory cortical neurons adapt to reverberation by adjusting their filtering properties in a manner consistent with dereverberation.

Although association between hearing impairment and dementia has been widely documented by epidemiological studies, the role of auditory sensory deprivation in cognitive decline remains to be fully understood. To address this issue we investigated the impact of hearing loss on the onset and time-course of cognitive decline in an animal model of Alzheimer’s disease (AD), that is the 3×Tg-AD mice and the underlying mechanisms. We found that hearing loss induced by noise exposure in the 3×Tg-AD mice before the phenotype is manifested caused persistent synaptic and morphological alterations in the auditory cortex. This was associated with earlier hippocampal dysfunction, increased tau phosphorylation, neuroinflammation, and redox imbalance, along with anticipated memory deficits compared to the expected time-course of the neurodegenerative phenotype. Our data suggest that a mouse model of AD is more vulnerable to central damage induced by hearing loss and shows reduced ability to counteract noise-induced detrimental effects, which accelerates the neurodegenerative disease onset.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca 2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca 2+ -permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca 2+ -impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro , and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC 50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin ( Nptn ) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice ( Nptn −/− ) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn −/− mice. Adult Nptn −/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn −/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn −/− mice. Conditional ablation of neuroplastin in Nptn lox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn Δlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca 2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.