Neuroplastin expression is essential for hearing and hair cell PMCA expression

Abstract

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 Nptnlox/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 NptnΔlox/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 Ca2+ 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.

Neuroplastin in Neuropsychiatric Diseases

“…In Nptn-deficient mice, PPI is severely impaired [50], although this could simply result from the profound hearing deficit of these mice [43], rather than processing deficits. Nevertheless, the significant reduction in paired-pulse facilitation in the auditory cortex of Nptn-deficient mice suggests altered cortical synaptic transmission [43]. In addition, the PPI deficit in heterozygous Nptn-deficient mice [50] points to potential central alterations as contributors to the phenotype.…”

“…Np55 is expressed in all brain regions and is the major isoform in rodent cerebellum [42]. In the inner ear of the mouse, Np55 is expressed in the stereocilia of the outer hair cells, in the cell bodies of inner hair cells, and in spiral ganglia cells [43]. The adhesive capacity of the Np65-specific Ig1 domain to undergo trans-homophilic binding was first described using an aggregation assay of microspheres coated with neuroplastin-Fc chimeric proteins [39].…”

“…In addition, numerous PMCA mutations are associated with human diseases and impairments, like deafness and ataxia (for review see: [100]). Interestingly, the genetically driven ablation of Nptn results in decreased PMCA levels and deafness in mice ( [43]; see below, Section 3.5.1 Deafness).…”

“…Pre-pulse inhibition (PPI) of the startle response is often considered as a characteristic in the diagnosis of schizophrenia [117]. In Nptn-deficient mice, PPI is severely impaired [50], although this could simply result from the profound hearing deficit of these mice [43], rather than processing deficits. Nevertheless, the significant reduction in paired-pulse facilitation in the auditory cortex of Nptn-deficient mice suggests altered cortical synaptic transmission [43].…”

“…Other Diseases Related to Neuroplastin 3.5.1. Deafness Deafness resulting from the loss of neuroplastin function has been studied using Nptndeficient and neuroplastin mutant mice [43,51,52]. It was proposed that Np55 expression by outer hair cells is required for cochlear amplification [52], and Carrott et al [51] proposed Np65-driven synaptogenesis by inner hair cells as necessary for hearing.…”