Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome.

Sensory processing abnormalities are frequently associated with autism spectrum disorders, but the underlying mechanisms are unclear. Here we studied auditory processing in a mouse model of Fragile X Syndrome (FXS), a leading known genetic cause of autism and intellectual disability. Both humans with FXS and the Fragile X mental retardation gene (Fmr1) knockout (KO) mouse model show auditory hypersensitivity, with the latter showing a strong propensity for audiogenic seizures (AGS) early in development. Because midbrain abnormalities cause AGS, we investigated whether the inferior colliculus (IC) of the Fmr1 KO mice shows abnormal auditory processing compared with wild-type (WT) controls at specific developmental time points. Using antibodies against neural activity marker c-Fos, we found increased density of c-Fos+ neurons in the IC, but not auditory cortex, of Fmr1 KO mice at P21 and P34 following sound presentation. In vivo single-unit recordings showed that IC neurons of Fmr1 KO mice are hyperresponsive to tone bursts and amplitude-modulated tones during development and show broader frequency tuning curves. There were no differences in rate-level responses or phase locking to amplitude-modulated tones in IC neurons between genotypes. Taken together, these data provide evidence for the development of auditory hyperresponsiveness in the IC of Fmr1 KO mice. Although most human and mouse work in autism and sensory processing has centered on the forebrain, our new findings, along with recent work on the lower brainstem, suggest that abnormal subcortical responses may underlie auditory hypersensitivity in autism spectrum disorders.NEW & NOTEWORTHY Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

Shaping of discrete auditory inputs to extramodular zones of the lateral cortex of the inferior colliculus.

The multimodal lateral cortex of the inferior colliculus (LCIC) exhibits a modular-extramodular micro-organization that is evident early in development. In addition to a set of neurochemical markers that reliably highlight its modular-extramodular organization (e.g. modules: GAD67-positive, extramodular zones: calretinin-positive, CR), mature projection patterns suggest that major LCIC afferents recognize and adhere to such a framework. In adult mice, distinct afferent projections appear segregated, with somatosensory inputs targeting LCIC modules and auditory inputs surrounding extramodular fields. Currently lacking is an understanding regarding the development and shaping of multimodal LCIC afferents with respect to its emerging modular-extramodular microarchitecture. Combining living slice tract-tracing and immunocytochemical approaches in GAD67-GFP knock-in mice, the present study characterizes the critical period of projection shaping for LCIC auditory afferents arising from its neighboring central nucleus (CNIC). Both crossed and uncrossed projection patterns exhibit LCIC extramodular mapping characteristics that emerge from initially diffuse distributions. Projection mismatch with GAD-defined modules and alignment with encompassing extramodular zones becomes increasingly clear over the early postnatal period (birth to postnatal day 12). CNIC inputs terminate almost exclusively in extramodular zones that express CR. These findings suggest multimodal LCIC inputs may initially be sparse and intermingle, prior to segregation into distinct processing streams. Future experiments are needed to determine the likely complex interactions and mechanisms (e.g. activity-dependent and independent) responsible for shaping early modality-specific LCIC circuits.

Apoptosis and proliferation in the inferior colliculus during postnatal development and epileptogenesis in audiogenic Krushinsky-Molodkina rats.

It is known that audiogenic seizure (AGS) expression is based on the activation of the midbrain structures such as the inferior colliculus (IC). It was demonstrated that excessive sound exposure during the postnatal developments of the IC in rats led to AGS susceptibility in adulthood, which correlated with underdevelopment of the IC. In adult rodents, noise overstimulation induced apoptosis in the IC. The purpose of this study was to investigate postnatal development of the IC in rats genetically prone to AGS and to check if audiogenic kindling would activate apoptosis and/or proliferation in the IC. In our study, we used inbred audiogenic Krushinsky-Molodkina (KM) rats, which are characterized by age-dependent seizure expression. Analysis of postnatal development showed the increased number of proliferating cells in the IC central nucleus of KM rats on the 14th postnatal day (P14) in comparison with those of Wistar rats. Moreover, we also observed increased apoptosis level and decreased general cell population in the IC central nucleus. These data pointed towards a delayed development of the IC in KM rats. Analysis of the IC central nucleus of KM rat after audiogenic kindling for a week, with one AGS per day, demonstrated dramatically increased cell death, which was accompanied with a reduction of general cell population. Audiogenic kindling also decreased proliferation in the IC central nucleus. However, a week after the last AGS, the number of proliferating cells was increased, which supposes a certain compensatory mechanism to prevent cell loss.

Alignment of EphA4 and ephrin-B2 expression patterns with developing modularity in the lateral cortex of the inferior colliculus.

In the multimodal lateral cortex of the inferior colliculus (LCIC), there are two neurochemically and connectionally distinct compartments, termed modular and extramodular zones. Modular fields span LCIC layer 2 and are recipients of somatosensory afferents, while encompassing extramodular domains receive auditory inputs. Recently, in developing mice, we identified several markers (among them glutamic acid decarboxylase, GAD) that consistently label the same modular set, and a reliable extramodular marker, calretinin, (CR). Previous reports from our lab show similar modular-extramodular patterns for certain Eph-ephrin guidance members, although their precise alignment with the developing LCIC neurochemical framework has yet to be addressed. Here we confirm in the nascent LCIC complementary GAD/CR-positive compartments, and characterize the registry of EphA4 and ephrin-B2 expression patterns with respect to its emerging modular-extramodular organization. Immunocytochemical approaches in GAD67-GFP knock-in mice reveal patchy EphA4 and ephrin-B2 domains that precisely align with GAD-positive LCIC modules, and are complementary to CR-defined extramodular zones. Such patterning was detectable neonatally, yielding discrete compartments prior to hearing onset. A dense plexus of EphA4-positive fibers filled modules, surrounding labeled ephrin-B2 and GAD cell populations. The majority of observed GABAergic neurons within modular boundaries were also positive for ephrin-B2. These results suggest an early compartmentalization of the LCIC that is likely instructed in part through Eph-ephrin guidance mechanisms. The overlap of developing LCIC neurochemical and guidance patterns is discussed in the context of its seemingly segregated multimodal input-output streams.

Modular-extramodular organization in developing multisensory shell regions of the mouse inferior colliculus.

The complex neuroanatomical connections of the inferior colliculus (IC) and its major subdivisions offer a juxtaposition of segregated processing streams with distinct organizational features. While the tonotopically layered central nucleus is well-documented, less is known about functional compartments in the neighboring lateral cortex (LCIC). In addition to a laminar framework, LCIC afferent-efferent patterns suggest a multimodal mosaic, consisting of a patchy modular network with surrounding extramodular domains. This study utilizes several neurochemical markers that reveal an emerging LCIC modular-extramodular microarchitecture. In newborn and post-hearing C57BL/6J and CBA/CaJ mice, histochemical and immunocytochemical stains were performed for acetylcholinesterase (AChE), nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), glutamic acid decarboxylase (GAD), cytochrome oxidase (CO), and calretinin (CR). Discontinuous layer 2 modules are positive for AChE, NADPH-d, GAD, and CO throughout the rostrocaudal LCIC. While not readily apparent at birth, discrete cell clusters emerge over the first postnatal week, yielding an identifiable modular network prior to hearing onset. Modular boundaries continue to become increasingly distinct with age, as surrounding extramodular fields remain largely negative for each marker. Alignment of modular markers in serial sections suggests each highlight the same periodic patchy network throughout the nascent LCIC. In contrast, CR patterns appear complementary, preferentially staining extramodular LCIC zones. Double-labeling experiments confirm that NADPH-d, the most consistent developmental modular marker, and CR label separate, nonoverlapping LCIC compartments. Determining how this emerging modularity may align with similar LCIC patch-matrix-like Eph/ephrin guidance patterns, and how each interface with, and potentially influence developing multimodal LCIC projection configurations is discussed.

Graded and discontinuous EphA-ephrinB expression patterns in the developing auditory brainstem.

Eph-ephrin interactions guide topographic mapping and pattern formation in a variety of systems. In contrast to other sensory pathways, their precise role in the assembly of central auditory circuits remains poorly understood. The auditory midbrain, or inferior colliculus (IC) is an intriguing structure for exploring guidance of patterned projections as adjacent subdivisions exhibit distinct organizational features. The central nucleus of the IC (CNIC) and deep aspects of its neighboring lateral cortex (LCIC, Layer 3) are tonotopically-organized and receive layered inputs from primarily downstream auditory sources. While less is known about more superficial aspects of the LCIC, its inputs are multimodal, lack a clear tonotopic order, and appear discontinuous, terminating in modular, patch/matrix-like distributions. Here we utilize X-Gal staining approaches in lacZ mutant mice (ephrin-B2, -B3, and EphA4) to reveal EphA-ephrinB expression patterns in the nascent IC during the period of projection shaping that precedes hearing onset. We also report early postnatal protein expression in the cochlear nuclei, the superior olivary complex, the nuclei of the lateral lemniscus, and relevant midline structures. Continuous ephrin-B2 and EphA4 expression gradients exist along frequency axes of the CNIC and LCIC Layer 3. In contrast, more superficial LCIC localization is not graded, but confined to a series of discrete ephrin-B2 and EphA4-positive Layer 2 modules. While heavily expressed in the midline, much of the auditory brainstem is devoid of ephrin-B3, including the CNIC, LCIC Layer 2 modular fields, the dorsal nucleus of the lateral lemniscus (DNLL), as well as much of the superior olivary complex and cochlear nuclei. Ephrin-B3 LCIC expression appears complementary to that of ephrin-B2 and EphA4, with protein most concentrated in presumptive extramodular zones. Described tonotopic gradients and seemingly complementary modular/extramodular patterns suggest Eph-ephrin guidance in establishing juxtaposed continuous and discrete neural maps in the developing IC prior to experience.

Structural changes in the adult rat auditory system induced by brief postnatal noise exposure.

In previous studies (Grécová et al., Eur J Neurosci 29:1921-1930, 2009; Bures et al., Eur J Neurosci 32:155-164, 2010), we demonstrated that after an early postnatal short noise exposure (8 min 125 dB, day 14) changes in the frequency tuning curves as well as changes in the coding of sound intensity are present in the inferior colliculus (IC) of adult rats. In this study, we analyze on the basis of the Golgi-Cox method the morphology of neurons in the IC, the medial geniculate body (MGB) and the auditory cortex (AC) of 3-month-old Long-Evans rats exposed to identical noise at postnatal day 14 and compare the results to littermate controls. In rats exposed to noise as pups, the mean total length of the neuronal tree was found to be larger in the external cortex and the central nucleus of the IC and in the ventral division of the MGB. In addition, the numerical density of dendritic spines was decreased on the branches of neurons in the ventral division of the MGB in noise-exposed animals. In the AC, the mean total length of the apical dendritic segments of pyramidal neurons was significantly shorter in noise-exposed rats, however, only slight differences with respect to controls were observed in the length of basal dendrites of pyramidal cells as well as in the neuronal trees of AC non-pyramidal neurons. The numerical density of dendritic spines on the branches of pyramidal AC neurons was lower in exposed rats than in controls. These findings demonstrate that early postnatal short noise exposure can induce permanent changes in the development of neurons in the central auditory system, which apparently represent morphological correlates of functional plasticity.

Antioxidant Treatments Recover the Alteration of Auditory-Evoked Potentials and Reduce Morphological Damage in the Inferior Colliculus after Perinatal Asphyxia in Rat.

Maturation of the auditory pathway is dependent on the central nervous system myelination and it can be affected by pathologies such as neonatal hypoxic ischemic (HI) encephalopathy. Our aim was to evaluate the functional integrity of the auditory pathway and to visualize, by histological and cellular methods, the damage to the brainstem using a neonatal rat model of HI brain injury. To carry out this morphofunctional evaluation, we studied the effects of the administration of the antioxidants nicotine, melatonin, resveratrol and docosahexaenoic acid after hypoxia-ischemia on the inferior colliculus and the auditory pathway. We found that the integrity of the auditory pathway in the brainstem was altered as a consequence of the HI insult. Thus, the auditory brainstem response (ABR) showed increased I-V and III-V wave latencies. At a histological level, HI altered the morphology of the inferior colliculus neurons, astrocytes and oligodendricytes, and at a molecular level, the mitochondria membrane potential and integrity was altered during the first hours after the HI and reactive oxygen species (ROS) activity is increased 12 h after the injury in the brainstem. Following antioxidant treatment, ABR interpeak latency intervals were restored and the body and brain weight was recovered as well as the morphology of the inferior colliculus that was similar to the control group. Our results support the hypothesis that antioxidant treatments have a protective effect on the functional changes of the auditory pathway and on the morphological damage which occurs after HI insult.

Development of intrinsic connectivity in the central nucleus of the mouse inferior colliculus.

The inferior colliculus (IC) in the mammalian midbrain is the major subcortical auditory integration center receiving ascending inputs from almost all auditory brainstem nuclei as well as descending inputs from the thalamus and cortex. In addition to these extrinsic inputs, the IC also contains a dense network of local, intracollicular connections, which are thought to provide gain control and contribute to the selectivity for complex acoustic features. However, in contrast to the organization of extrinsic IC afferents, the development and functional organization of intrinsic connections in the IC has remained poorly understood. Here we used laser-scanning photostimulation with caged glutamate to characterize the spatial distribution and strength of local synaptic connections in the central nucleus of the inferior colliculus of newborn mice until after hearing onset (P2-P22). We demonstrate the presence of an extensive excitatory and inhibitory intracollicular network already at P2. Excitatory and inhibitory synaptic maps to individual IC neurons formed continuous maps that largely overlapped with each other and that were aligned with the presumed isofrequency axis of the central nucleus of the IC. Although this characteristic organization was present throughout the first three postnatal weeks, the size of input maps was developmentally regulated as input maps underwent an expansion during the first week that was followed by a dramatic refinement after hearing onset. These changes occurred in parallel for excitatory and inhibitory input maps. However, the functional elimination of intrinsic connections was greater for excitatory than for inhibitory connections, resulting in a predominance of intrinsic inhibition after hearing onset.

Acoustical enrichment during early postnatal development changes response properties of inferior colliculus neurons in rats.

The structure and function of the auditory system may be influenced by acoustic stimulation, especially during the early postnatal period. This study explores the effects of an acoustically enriched environment applied during the third and fourth week of life on the responsiveness of inferior colliculus neurons in rats. The enrichment comprised a spectrally and temporally modulated complex sound reinforced with several target acoustic stimuli, one of which triggered a reward release. The exposure permanently influenced neuronal representation of the sound frequency and intensity, resulting in lower excitatory thresholds at neuronal characteristic frequency, an increased frequency selectivity, larger response magnitudes, steeper rate-intensity functions and an increased spontaneous activity. The effect was general and non-specific, spanning the entire hearing range - no changes specific to the frequency band of the target stimuli were found. The alterations depended on the activity of animals during the enrichment - a higher activity of rats in the stimulus-reward paradigm led to more profound changes compared with the treatment when the stimulus-reward paradigm was not used. Furthermore, the exposure in early life led to permanent changes in response parameters, whereas the application of the same environment in adulthood influenced only a subset of the examined parameters and had only a temporary effect. These findings indicate that a rich and stimulating acoustic environment during early development, particularly when reinforced by positive feedback, may permanently affect signal processing in the subcortical auditory nuclei, including the excitatory thresholds of neurons and their frequency and intensity resolution.

Development of myelination and cholinergic innervation in the central auditory system of a prosimian primate (Otolemur garnetti).

Change in the timeline of neurobiological growth is an important source of biological variation, and thus phenotypic evolution. However, no study has to date investigated sensory system development in any of the prosimian primates that are thought to most closely resemble our earliest primate ancestors. Acetylcholine (ACh) is a neurotransmitter critical to normal brain function by regulating synaptic plasticity associated with attention and learning. Myelination is an important structural component of the brain because it facilitates rapid neuronal communication. In this work we investigated the expression of acetylcholinesterase (AChE) and the density of myelinated axons throughout postnatal development in the inferior colliculus (IC), medial geniculate complex (MGC), and auditory cortex (auditory core, belt, and parabelt) in Garnett's greater galago (Otolemur garnetti). We found that the IC and MGC exhibit relatively high myelinated fiber length density (MFLD) values at birth and attain adult-like values by the species-typical age at weaning. In contrast, neocortical auditory fields are relatively unmyelinated at birth and only attain adult-like MFLD values by the species-typical age at puberty. Analysis of AChE expression indicated that, in contrast to evidence from rodent samples, the adult-like distribution of AChE in the core area of auditory cortex, dense bands in layers I, IIIb/IV, and Vb/VI, is present at birth. These data indicate the differential developmental trajectory of central auditory system structures and demonstrate the early onset of adult-like AChE expression in primary auditory cortex in O. garnetti, suggesting the auditory system is more developed at birth in primates compared to rodents.

Postnatal development of synaptic properties of the GABAergic projection from the inferior colliculus to the auditory thalamus.

The development of auditory temporal processing is important for processing complex sounds as well as for acquiring reading and language skills. Neuronal properties and sound processing change dramatically in auditory cortex neurons after the onset of hearing. However, the development of the auditory thalamus or medial geniculate body (MGB) has not been well studied over this critical time window. Since synaptic inhibition has been shown to be crucial for auditory temporal processing, this study examined the development of a feedforward, GABAergic connection to the MGB from the inferior colliculus (IC), which is also the source of sensory glutamatergic inputs to the MGB. IC-MGB inhibition was studied using whole cell patch-clamp recordings from rat brain slices in current-clamp and voltage-clamp modes at three age groups: a prehearing group [postnatal day (P)7-P9], an immediate posthearing group (P15-P17), and a juvenile group (P22-P32) whose neuronal properties are largely mature. Membrane properties matured substantially across the ages studied. GABAA and GABAB inhibitory postsynaptic potentials were present at all ages and were similar in amplitude. Inhibitory postsynaptic potentials became faster to single shocks, showed less depression to train stimuli at 5 and 10 Hz, and were overall more efficacious in controlling excitability with age. Overall, IC-MGB inhibition becomes faster and more precise during a time period of rapid changes across the auditory system due to the codevelopment of membrane properties and synaptic properties.

Ephrin-B2 reverse signaling is required for topography but not pattern formation of lateral superior olivary inputs to the inferior colliculus.

Graded and modular expressions of Eph-ephrins are known to provide positional information for the formation of topographic maps and patterning in the developing nervous system. Previously we have shown that ephrin-B2 is expressed in a continuous gradient across the tonotopic axis of the central nucleus of the inferior colliculus (CNIC), whereas patterns are discontinuous and modular in the lateral cortex of the IC (LCIC). The present study explores the involvement of ephrin-B2 signaling in the development of projections to the CNIC and LCIC arising from the lateral superior olivary nuclei (LSO) prior to hearing onset. Anterograde and retrograde fluorescent tracing methods in neonatal fixed tissue preparations were used to compare topographic mapping and the establishment of LSO layers/modules in wild-type and ephrin-B2(lacZ/+) mice (severely compromised reverse signaling). At birth, pioneer LSO axons occupy the ipsilateral IC in both groups but are delayed contralaterally in ephrin-B2(lacZ/+) mutants. By the onset of hearing, both wild-type and mutant projections form discernible layers bilaterally in the CNIC and modular arrangements within the ipsilateral LCIC. In contrast, ephrin-B2(lacZ/+) mice lack a reliable topography in LSO-IC projections, suggesting that fully functional ephrin-B2 reverse signaling is required for normal projection mapping. Taken together, these ephrin-B2 findings paired with known coexpression of EphA4 suggest the importance of these signaling proteins in establishing functional auditory circuits prior to experience.

Developmental changes of the protein repertoire in the rat auditory brainstem: a comparative proteomics approach in the superior olivary complex and the inferior colliculus with DIGE and iTRAQ.

Protein profiles of developing neural circuits undergo manifold changes. The aim of this proteomic analysis was to quantify postnatal changes in two auditory brainstem areas in a comparative approach. Protein samples from the inferior colliculus (IC) and the superior olivary complex (SOC) were obtained from neonatal (P4) and young adult (P60) rats. The cytosolic fractions of both areas were examined by 2-D DIGE, and the plasma membrane-enriched fraction of the IC was analyzed via iTRAQ. iTRAQ showed a regulation in 34% of the quantified proteins. DIGE revealed 12% regulated spots in both the SOC and IC and, thus, numeric congruency. Although regulation in KEGG pathways displayed a similar pattern in both areas, only 13 of 71 regulated DIGE proteins were regulated in common, implying major area-specific differences. 89% of regulated glycolysis/gluconeogenesis and citrate cycle proteins were up-regulated in the SOC or IC, suggesting a higher energy demand in adulthood. Seventeen cytoskeleton proteins were regulated, consistent with complex morphological reorganization between P4 and P60. Fourteen were uniquely regulated in the SOC, providing further evidence for area-specific differences. Altogether, we provide the first elaborate catalog of proteins involved in auditory brainstem development, several of them possibly of particular developmental relevance.

EphA4 and ephrin-B2 expression patterns during inferior colliculus projection shaping prior to experience.

Central processing of complex auditory tasks requires elaborate circuitry. The auditory midbrain, or inferior colliculus (IC), epitomizes such precise organization, where converging inputs form discrete, tonotopically-arranged axonal layers. Previously in rat, we established that shaping of multiple afferent patterns in the IC central nucleus (CNIC) occurs prior to experience. This study implicates an Eph receptor tyrosine kinase and a corresponding ephrin ligand in signaling this early topographic registry. We report that EphA4 and ephrin-B2 expression patterns in the neonatal rat and mouse IC correlate temporally and spatially with that of developing axonal layers. DiI-labeling confirms projections arising from the lateral superior olive (LSO) form frequency-specific layers within the ipsilateral and contralateral mouse CNIC, as has been described in other species. Immunohistochemistry (EphA4 and ephrin-B2) and ephrin-B2 lacZ histochemistry reveal clear gradients in expression across the tonotopic axis, with most concentrated labeling observed in high-frequency, ventromedial aspects of the CNIC. Discrete patches of labeling were also discernible in the external cortex of the IC (ECIC; EphA4 patches in rat, ephrin-B2 patches in mouse). Observed gradients in the CNIC and compartmentalized ECIC expression persisted through the first postnatal week, before becoming less intense and more homogeneously distributed by the functional onset of hearing. EphA4 and ephrin-B2-positive neurons were evident in several auditory brainstem nuclei known to send patterened inputs to the IC. These findings suggest the involvement of cell-cell EphA4 and ephrin-B2 signaling in establishing order in the developing IC.

Noise exposure during early development impairs the processing of sound intensity in adult rats.

During the early postnatal development of rats, the structural and functional maturation of the central auditory nuclei strongly relies on the natural character of the incoming neural activity. Even a temporary deprivation in the critical period results in a deterioration of neuronal responsiveness in adult animals. We demonstrate that besides the poorer frequency selectivity of neurons in the impaired animals reported previously [Grecova et al. (2009)Eur. J. Neurosci. 29, 1921-1930], the neuronal representation of sound intensity is significantly affected. Rate-intensity functions of inferior colliculus neurons were recorded in anaesthetized adult rats that were exposed to intense noise at postnatal day 14, and compared with those obtained in age-matched controls. Although the response thresholds were similar in the exposed and control rats, the neurons in the exposed animals had a longer first-spike latency, a narrower dynamic range, lower maximum response magnitudes and a steeper slope of the rate-intensity functions. The percentage of monotonic neurons was significantly lower in the exposed animals. The observed anomalies were confined to the mid- and high-frequency regions, whereas no significant changes were found in the low-frequency neurons. The altered parameters of the individual rate-intensity functions led also to differences in the cumulative responses. We conclude that a brief noise exposure during the critical period leads to a frequency-dependent alteration of the sound intensity representation in the inferior colliculus of adult rats. The results suggest that such impairments may appear in individuals with normal hearing thresholds, but with a history of noise exposure very early in childhood.

[GluR2 expression in the developing rat inferior colliculus and the relationship with development of synapse].

OBJECTIVE: To observe the GluR2 expression in rat inferior colliculus (IC) in different developmental stages, and to investigate its developmental change and relationship with the synapse development. METHOD: The expression of GluR2 and synaptophysin(SYP) in IC were detected by double immunofluorescence method. RESULT: (1) All sorts of neurons in IC expressed GluR2 in every postnatal groups, and the GluR2 expression in P6w groups was higher than that in other groups. (2) The expression of GluR2 were different in different subnucleus of IC. (3) All sorts of neurons in IC expressed SYP in every postnatal groups, and the SYP expression in P6w groups was higher than others. (4) The expressions of GluR2 consistent with the expression of SYP in IC. CONCLUSION: The developmental changes of GluR2 and SYP expression in the rat IC may be involved in the development and plasticity of auditory center.

Temporal distribution of mRNA expression levels of various genes in the developing human inferior colliculus.

The inferior colliculus (IC) is a major binaural integration center in the auditory pathway. Interestingly, studies on the prenatal development of the human IC are lacking. During development of the nervous system a large repertoire of proteins is involved in transforming simple neuroblast cells into functional elements of the adult neural circuits. The present study reports on the mRNA levels produced by 12 genes involved in pre- [12-29 weeks of gestation (WG)], postnatal [40 postnatal days (PND) as well as 2 and 5 postnatal months (PNM)] developing human IC. The mRNA expression levels of nestin, vimentin, GFAP and DCX during 12-24 WG indicate the stages of neurogenesis, migration and differentiation of the human fetal IC. A decrease in the GAP-43 mRNA levels along with an increase in synaptophysin and PSD-95 mRNA levels during late gestational ages (24-29 WG) suggests the formation of primitive contacts by neurons with their targets and the onset of synapse formation. Expression levels of EGAD mRNA were transient with an increase in the early gestational ages, whereas that of GAD-67 mRNA increased in late gestational ages, indicating the changing role of GABA from a trophic factor to that of a neurotransmitter. High levels of BDNF, NT-3 and MBP mRNA in the late gestational ages reveal that the human IC undergoes neuronal maturation, synaptogenesis and myelination by 29 WG. Therefore, it may be suggested that the morphological maturation of the human IC occurs between 22 and 29 WG and that this period appears to be critical in the shaping of adult-like physiological attributes.

Brief exposure of juvenile rats to noise impairs the development of the response properties of inferior colliculus neurons.

Temporary impairment of the auditory periphery during the sensitive period of postnatal development of rats may result in a deterioration of neuronal responsiveness in the central auditory nuclei of adult animals. In this study, juvenile rats (postnatal day 14) were exposed for 8 min to intense broad-band noise; at the age of 3-6 months, the excitatory and inhibitory response areas of neurons in the central nucleus of the inferior colliculus were recorded under ketamine-xylazine anaesthesia in these animals and compared with those of age-matched controls. The response thresholds were similar in the exposed and control animals. The frequency selectivity of low-frequency neurons was comparable in both groups; however, high-frequency neurons had significantly wider excitatory response areas in the exposed rats, indicating disrupted development of high-frequency hearing. Forty-one per cent and 25% of neurons in exposed animals and in controls, respectively, lacked a distinct inhibitory area; these neurons had similar frequency selectivity in the exposed and control rats. As the presence of an inhibitory sideband was associated with sharper frequency tuning in both groups, it appears that lateral inhibition substantially influences neuronal frequency selectivity. If present, the inhibitory areas had comparable bandwidths in both groups; however, they were shifted to the side in the exposed animals, allowing the expansion of the excitatory areas. The results indicate that a brief exposure of juvenile rats to noise leads to a significant worsening of the frequency selectivity of inferior colliculus neurons in adult animals; the poorer frequency selectivity may be due to missing or displaced inhibitory sidebands.

Stereological investigation and expression of calcium-binding proteins in developing human inferior colliculus.

The mammalian inferior colliculus (IC) is a major relay nucleus in the auditory pathway. Prenatal development of the human IC has been inadequately studied. The present study reports the morphometric development and maturation of the human IC using unbiased stereology, in 18 aborted fetuses of various gestational ages (12-29 weeks) and two babies aged 40 postnatal days (PND) and 5 months (that died of postoperative complications). It also demonstrates the functional maturation of the IC by examining the expression of calcium-binding proteins--parvalbumin (PV) and calbindin (CB). There was a significant increase in the total number of neurons and glia from 18 weeks of gestation (WG). The glia and neuron volume increased significantly from 16 WG to 22 WG, respectively. The total volume of IC also increased significantly from 18 WG onwards. On the other hand, the number and volume of undifferentiated cell bodies across all ages decreased significantly. Expression of CB was concentrated in the dorsal cortex while that of PV was mainly confined to the central nucleus of the IC, possibly indicating an early segregation of parallel processing of information in the auditory pathways. Intense staining for CB in the soma and dendrites appeared earlier than that of the PV. The morphological maturation appeared to overlap the onset of functional maturation suggesting an activity-dependent mechanism in the development of IC.