Activation of Metabotropic Glutamate Receptors Regulates Ribosomes of Cochlear Nucleus Neurons

Abstract

The brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through cochlear ablation results in the eventual death of approximately 30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). One early change following deafness is an alteration in NM ribosomes, evidenced both by a decrease in protein synthesis and reduction in antigenicity for Y10B, a monoclonal antibody that recognizes a ribosomal epitope. Previous studies have shown that mGluR activation is necessary to maintain Y10B antigenicity and NM viability. What is still unclear, however, is whether or not mGluR activation is sufficient to prevent deafness-induced changes in these neurons, or if other activity-dependent factors are also necessary. The current study investigated the ability of mGluR activation to regulate cochlear nucleus ribosomes in the absence of auditory nerve input. In vitro methods were employed to periodically pressure eject glutamate or mGluR agonists over neurons on one side of a slice preparation leaving the opposite side of the same slice untreated. Immunohistochemistry was then performed using Y10B in order to assess ribosomal changes. Application of glutamate and both group I and II selective mGluR agonists effectively rescued ribosomal antigenicity on the treated side of the slice in comparison to ribosomes on the untreated side. These findings suggest that administration of mGluR agonists is sufficient to reduce the early interruption of normal ribosomal integrity that is typically seen following loss of auditory nerve activity.

Neuroglial Involvement in Abnormal Glutamate Transport in the Cochlear Nuclei of the Igf1−/− Mouse

“…mGluR2 is also expressed in the cochlear nuclei while the expression of mGluR4 and mGluR7 remains unclear (Lu, 2014). In vivo and in vitro studies in the chick cochlear nucleus, nucleus magnocellularis, have demonstrated that pharmacological blockade of groups I and II mGluR activation provokes neuronal degeneration, suggesting a pivotal role for these receptors in regulating neuronal survival (Nicholas and Hyson, 2004; Diaz et al, 2009; Carzoli and Hyson, 2011, 2014). The activation of these receptors also regulates glutamate uptake at the cochlear nucleus-auditory nerve synapse, preventing the excitotoxic accumulation of extracellular glutamate (Carzoli and Hyson, 2014).…”

“…In vivo and in vitro studies in the chick cochlear nucleus, nucleus magnocellularis, have demonstrated that pharmacological blockade of groups I and II mGluR activation provokes neuronal degeneration, suggesting a pivotal role for these receptors in regulating neuronal survival (Nicholas and Hyson, 2004; Diaz et al, 2009; Carzoli and Hyson, 2011, 2014). The activation of these receptors also regulates glutamate uptake at the cochlear nucleus-auditory nerve synapse, preventing the excitotoxic accumulation of extracellular glutamate (Carzoli and Hyson, 2014). Whole cell recordings in brain slice preparations demonstrated that the activity of mGluRs suppresses GABAergic transmission (Lu, 2007), highlighting their role in achieving balanced excitation and inhibition in the nucleus magnocellularis.…”

“…The expression of mGluRs in the mammalian and avian auditory system has been seen to vary depending on the specific nucleus and the cell types they contain (Petralia et al, 2000; Lu, 2014). For example, mGluR1 and mGluR2 mRNA and protein has been detected in both the dorsal and ventral subdivisions of the cochlear nuclei, most intensely in the dorsal cochlear nucleus (DCN) where they seem to be located both pre- and post-synaptically (Bilak and Morest, 1998; Petralia et al, 2000; Kemmer and Vater, 2001; Nicholas and Hyson, 2004; Diaz et al, 2009; Martinez-Galan et al, 2010; Carzoli and Hyson, 2011, 2014). However, there is some controversy regarding the expression of the mGluR4 and mGluR7 subunits, and little information is available about mGluR3, mGluR5, mGluR6 and mGluR8 (Lu, 2014).…”

Anatomy and Physiology of Metabotropic Glutamate Receptors in Mammalian and Avian Auditory System

“…They found that deprivation of the auditory nerve input disrupts protein synthesis in NM neurons [123]. Further studies have shown that this activity-dependent regulation of protein synthesis relies on activity of mGluRs [124,125], but not involve iGluRs [126]. Specifically, group I and II mGluRs are required to maintain protein synthesis in NM neurons, because blocking either group I or II mGluRs eliminates activity-dependent regulation of ribosomes in vitro [127,128] as well as in vivo [129].…”