Aging and Central Auditory Disinhibition: Is It a Reflection of Homeostatic Downregulation or Metabolic Vulnerability?

Abstract

Aging-related changes have been identified at virtually every level of the central auditory system. One of the most common findings across these nuclei is a loss of synaptic inhibition with aging, which has been proposed to be at the heart of several aging-related changes in auditory cognition, including diminished speech perception in complex environments and the presence of tinnitus. Some authors have speculated that downregulation of synaptic inhibition is a consequence of peripheral deafferentation and therefore is a homeostatic mechanism to restore excitatory/inhibitory balance. As such, disinhibition would represent a form of maladaptive plasticity. However, clinical data suggest that deafferentation-related disinhibition tends to occur primarily in the aged brain. Therefore, aging-related disinhibition may, in part, be related to the high metabolic demands of inhibitory neurons relative to their excitatory counterparts. These findings suggest that both deafferentation-related maladaptive plastic changes and aging-related metabolic factors combine to produce changes in central auditory function. Here, we explore the arguments that downregulation of inhibition may be due to homeostatic responses to diminished afferent input vs. metabolic vulnerability of inhibitory neurons in the aged brain. Understanding the relative importance of these mechanisms will be critical for the development of treatments for the underlying causes of aging-related central disinhibition.

Keywords: GABA; aging; auditory; glycine; metabolism; mitochondria; presbycusis; tinnitus.

Figure 1

(A) Mean glutamic acid decarboxylase (GAD) levels measured via Western blotting of the cytosolic fractions of inferior colliculus homogenates at various times after acoustic trauma. (B) Representative autoradiograms from the Western blots taken from the membrane fractions of the inferior colliculus samples at times after acoustic trauma. (C) and (D) Color-enhanced images of (³H) muscimol binding in representative rats without acoustic trauma (C) and 30 days after acoustic trauma (D), showing the increase in muscimol binding in the inferior colliculus post-trauma. IC = inferior colliculus. Reproduced with permission from [61]. * p < 0.05.

Figure 2

(A,B) Flavoprotein autofluorescence responses after electrical stimulation of the thalamocortical afferents (triangle) and activation of the auditory cortex under conditions of GABA_A-receptor blockade (using SR95531, in (A) or under control conditions (B). Scale bar = 1 mm. (C) Ratio of the response to SR9551 to control in young compared to aged mice, indicating a lack of sensitivity to GABA_A blockade in the aging auditory cortex. Reproduced with permission from [69].

Figure 3

Possible mechanisms for aging-related changes of the GABAergic system. The aging-related downregulation of inhibition of the central auditory system could be mediated by plastic changes (red arrows), metabolic stress and a declining of mitochondrial function (solid green arrows), or a coupling between plastic and metabolic changes (yellow arrows). The aging-related metabolic stress of the cochlea could result in peripheral deafferentation that could be a mechanism to couple metabolic stress with adaptive plasticity (gray arrow).