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Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2and Plxna4as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases. In adult Plxna2−/−but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2−/−mice revealed deficits in associative learning, sociability, and sensorimotor gating—traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2and RAP1associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health.

OTO-201 can provide sustained release to the middle ear and effectively treat otitis media, when compared with FDA-approved ciprofloxacin otic drop formulations.

To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated.

OBJECTIVE To investigate the ototoxic potential of ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%, after administration to the guinea pig middle ear. DESIGN Fifty guinea pigs were randomly assigned to 4 test groups of 10 animals each and 2 control groups of 5 animals each. The 4 test groups were treated twice daily for 4 weeks with 10 μL of (1) ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%; (2) ciprofloxacin hydrochloride, 1.0%, plus dexamethasone, 0.3%; (3) ciprofloxacin hydrochloride, 0.3%, or (4) vehicle. The positive and negative control groups were treated with neomycin sulfate, 10%, or isotonic sodium chloride solution, respectively. SETTING Academic research laboratory. INTERVENTIONS Study animals were implanted with a drug delivery cannula to the middle ear, terminating in the round window niche for direct delivery to the round window membrane. MAIN OUTCOME MEASURES Auditory brainstem responses were collected at baseline and following 2 and 4 weeks of dosing. At the termination of the study, inner ear tissues were evaluated microscopically. RESULTS No biologically relevant hearing losses were observed after either 2 or 4 weeks of treatment with vehicle, ciprofloxacin alone, or combinations of ciprofloxacin plus dexamethasone. Examination of the organ of Corti revealed normal hair cell counts in all animals that received isotonic sodium chloride solution, vehicle, ciprofloxacin, or combinations of ciprofloxacin and dexamethasone. Conversely, the neomycin sulfate positive control group demonstrated a significant elevation in hearing threshold and profound hair cell loss (P <.001, P  = .02, and P <.001 at 2, 8, and 16 kHz, respectively). CONCLUSION The results of this preclinical study support the safety of ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%, for clinical use in the open middle ear cavity.Arch Otolaryngol Head Neck Surg. 2009;135(6):575-580--

The genetic and physiological characterization of circling, hearing-impaired mouse mutants has greatly facilitated our understanding of non-syndromic sensorineural deafness, the most common form of hereditary human hearing loss. Here we report the first phenotypic characterization of three alleles of Ames waltzer (av). Neither electrical potentials (auditory brainstem response) nor behavioral responses to sound could be evoked in any of the three alleles at any age or frequency. However, the endocochlear potential was found to be normal, indicating that the primary pathology is not in the stria vascularis. To determine the earliest changes and help identify the primary causes of deafness in av, we performed morphological studies in 15–16 day old mutants, just prior to the maturation of the cochlea. Although av2Jis slightly more affected than the other two alleles, our studies show a high similarity between all three alleles. The first detectable changes are observed in the stereocilia and cytoplasm of hair cells, and in the cellular shape and microvilli of supporting cells. These changes are followed by degeneration of the cochlear and vestibular neuroepithelium.

OBJECTIVE: To examine possible age-related differences in auditory sensitivity and cochlear vascular properties. DESIGN: This study is designed to provide information regarding cochlear function using physiological and audiological measures. Each animal underwent intravital microscopic evaluation of red blood cell velocity, vessel diameter, and vascular permeability in the second turn of the cochlear lateral wall. Auditory brain stem responses were used to determine hearing sensitivity. SUBJECTS: Four age ranges of male Fischer rats were studied: young, 2 to 4 months (n=9); mid-young, 9 to 11 months (n=8); mid-old, 18 to 20 months (n=6); and old, 30 to 34 months (n=10). RESULTS: Auditory brain stem response testing showed an age-related decrease in auditory sensitivity. Intravital microscopic analysis showed age-related statistically significant decreases in red blood cell velocity and increased vascular permeability with a trend for reduced capillary diameters. CONCLUSIONS: The process of aging is associated with many biochemical and physiological changes that include decrease in cellular water concentration, ionic changes, and decreased elasticity of cellular membranes. One contributing factor to this process may be altered vascular characteristics, such as reduced flow and vascular plasticity, as well as increased vascular permeability. These age-related changes may result in reductions in oxygen and nutrient delivery, and also waste elimination. Our results suggest that progressive age-associated vascular compromise may be a contributing factor in presbycusis.Arch Otolaryngol Head Neck Surg. 1996;122:1221-1226

This report provides a detailed analysis of tone‐evoked velocity responses of basilar membrane (BM) motion measured in the basal turn of the guinea pig cochlea. A laser Doppler vibrometer, coupled to a compound microscope, measured the velocity of reflective microbeads placed onto the scala tympani surface of the BM. The velocity responses of the stapes footplate were also determined, allowing the calculation of a BM transfer function. The normal transfer function is compared to that seen with cochlear ‘‘insensitivity’’ and postmortem. This comparison results in measures of the active process contribution to the magnitude and phase of the BM transfer function. It was found that the active process contributed as much as 65 dB of ‘‘gain’’ and 270° of phase lag at the best frequency. Other details about features of input/output velocity functions and the derived mechanical frequency‐tuning curve at a criterion of 50 μm/s are analyzed. © 1996 Acoustical Society of America.

Cis-diamminedichloroplatinum (cisplatin), a divalent platinum compound and cell-cycle nonspecific chemotherapeutic agent, produces a permanent high-frequency sensorineural hearing loss and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. Synthetic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objectives of this study were to analyze the potential cochlear and nephrotoxic effects of two synthetic platinum analogs presently in phases I and II of clinical trials, CBDCA [JM-8 or cis-diammine, 1,1-cyclobutane dicarboxylato (2)-0,01-platinum (NSC-241240)] and CHIP [JM-9 or cis-dichloro-trans-dihydroxybisisopropylamine platinum IV (NSC-256927)]. Cytocochleography, auditory brain-stem evoked response (ABR), double-blind light microscopy of renal tissues, and gamma emission analysis of 195mpt localization in viscera and inner ear were employed in the evaluation of cisplatin and platinum analogs (JM-8 and JM-9) in adult guinea pigs. Final results indicate that the investigational chemotherapeutic analogs CBDCA (JM-8) and CHIP (JM-9) do notproduce the ototoxicity and nephrotoxicity characteristic of cisplatin. Furthermore, these findings demonstrate 195mpt localization in the vestibular labyrinth and confirm previous platinum distribution studies in the organ of Corti and stria vascularis tissues.

Recordings of dc and ac receptor potentials from pigmented guinea pig inner hair cells indicate strong responses to the 2f1‐f2 intermodulation tone when f1 and f2 are greater than the hair cell characteristic frequency and do not cause a response when given individually. The effective magnitude of this cubic distortion product (CDP) was about 25–30 dB below equal sound level primaries over a 20–30‐dB range of their sound levels. The relative strength of the CDP declined at a rate greater than 180‐dB/oct separation of the primaries. When magnitude of f1 or f2 was held constant, the growth of CDP was nonmonotonic, exhibiting a distinct maximum. With a constant level of f1 or f2, optimal CDP was produced when the level of f2 was 10–15 dB greater than f1. Strong two‐tone suppression from the primaries has a role in shaping the CDP growth. The ac receptor potentials of the CDP show a 150°–200° phase shift when the primaries are increased over a 50‐dB range. These results support the hypothesis of a propagated CDP in the cochlea and are consistent with the major features of related studies of human psychoacoustic experiments, afferent nerve neural rate functions, and ear canal distortion products.

Cis-diamminedichloroplatinum (cisplatin), a divalent platinum compound and cell-cycle nonspecific chemotherapeutic agent, produces a permanent high-frequency sensorineural hearing loss and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. Synthetic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objectives of this study were to analyze the potential cochlear and nephrotoxic effects of two synthetic platinum analogs presently in phases I and II of clinical trials, CBDCA [JM-8 or cis-diammine, 1,1-cyclobutane dicarboxylato (2)-0,01-platinum (NSC-241240)] and CHIP [JM-9 or cis-dichloro-trans-dihydroxybisisopropylamine platinum IV (NSC-256927)]. Cytocochleography, auditory brain-stem evoked response (ABR), double-blind light microscopy of renal tissues, and gamma emission analysis of 195mpt localization in viscera and inner ear were employed in the evaluation of cisplatin and platinum analogs (JM-8 and JM-9) in adult guinea pigs. Final results indicate that the investigational chemotherapeutic analogs CBDCA (JM-8) and CHIP (JM-9) do notproduce the ototoxicity and nephrotoxicity characteristic of cisplatin. Furthermore, these findings demonstrate 195mpt localization in the vestibular labyrinth and confirm previous platinum distribution studies in the organ of Corti and stria vascularis tissues.

Voltage recorded from an electrode on the round window (RW) of guinea pig has characteristics that reflect the activity of auditory‐nerve fibers in the absence of acoustic stimulation. Fast Fourier transformation (FFT) of the noise recorded from the RW electrode shows a broad spectral peak from 0.8–1.0 kHz. The magnitude of the biological noise is increased by high‐frequency, bandlimited acoustic noise stimulation. Pure tones can suppress or enhance the spectral components around 0.8–1.0 kHz depending on frequency and intensity. Kainic acid applied to the intact RW membrane eliminates the biological noise (and the evoked cochlear whole‐nerve responses) without alteration of the cochlear microphonic or the summating potential. The spectral characteristics of the biological noise seem to be related to the elemental waveform contributed by the individual auditory‐nerve fibers to the voltage recorded at the RW electrode [Kiang etal., Electrocochleography, edited by R. J. Ruben, C. Elbering, and G. Solomon (University Park, Baltimore, 1976)].