Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system

Abstract

Aging and acoustic trauma may result in partial peripheral deafferentation in the central auditory pathway of the mammalian brain. In accord with homeostatic plasticity, loss of sensory input results in a change in pre- and postsynaptic GABAergic and glycinergic inhibitory neurotransmission. As seen in development, age-related changes may be activity dependent. Age-related presynaptic changes in the cochlear nucleus include reduced glycine levels, while in the auditory midbrain and cortex, GABA synthesis and release are altered. Presumably, in response to age-related decreases in presynaptic release of inhibitory neurotransmitters, there are age-related postsynaptic subunit changes in the composition of the glycine (GlyR) and GABA(A) (GABA(A)R) receptors. Age-related changes in the subunit makeup of inhibitory pentameric receptor constructs result in altered pharmacological and physiological responses consistent with a net down-regulation of functional inhibition. Age-related functional changes associated with glycine neurotransmission in dorsal cochlear nucleus (DCN) include altered intensity and temporal coding by DCN projection neurons. Loss of synaptic inhibition in the superior olivary complex (SOC) and the inferior colliculus (IC) likely affect the ability of aged animals to localize sounds in their natural environment. Age-related postsynaptic GABA(A)R changes in IC and primary auditory cortex (A1) involve changes in the subunit makeup of GABA(A)Rs. In turn, these changes cause age-related changes in the pharmacology and response properties of neurons in IC and A1 circuits, which collectively may affect temporal processing and response reliability. Findings of age-related inhibitory changes within mammalian auditory circuits are similar to age and deafferentation plasticity changes observed in other sensory systems. Although few studies have examined sensory aging in the wild, these age-related changes would likely compromise an animal's ability to avoid predation or to be a successful predator in their natural environment.

Fig. 1

A schematic drawing of the ascending auditory pathway in rat. The auditory nerve carries signals from hair cells of cochlea into cochlear nucleus, where acoustic information projects to other brainstem auditory nuclei. Signals from ventral cochlear nucleus (VCN) travel to the superior olivary complex (SOC) which is comprised of three important subgroups (LSO, MSO, MNTB) involved in the localization of sound in space. The SOC sends projections primarily to the inferior colliculus (IC), while information from dorsal cochlear nucleus (DCN) projects directly to IC. From IC, auditory messages proceed to medial geniculate body (MGB, a subregion of thalamus), which in turn projects to primary auditory cortex (A1), located in the temporal lobe of cerebrum.

Fig. 2

Comparison of age-related haircell loss and changes in auditory brainstem response (ABR) thresholds of FBN and F344 rats. (A) Cochleograms of aged F344 (24mos, n = 8) and aged FBN (32mos, n = 7) rats showing percent hair cells relative to young rats. The pattern of age-related hair cell loss was different between the two strains. Aged FBN rats lost few IHCs, while aged F344 rats displayed small IHC losses ( < 10%) throughout the cochlea with pronounced increase in IHC loss near the basal end. F344 exhibited U-shaped loss of OHCs with the greatest losses (as high as 70%) confined to apical and basal turns. Low levels of OHC losses were observed throughout the F344 cochlea. FBN rats had significant OHC losses starting at the apex, which tapered to moderate losses in the basal regions. The pattern of OHC loss resembles those described by Keithley and colleagues (1992) for Brown Norway spiral ganglion cells. (B) ABR thresholds for young and aged F344 (3mos, n = 28; 24mos, n = 18) and FBN rats (4mos, n = 11; 32mos, n = 10) are shown. F344 rat thresholds were lower at 4 and 8 kHz than 16 and 24 kHz. FBN rats displayed a significantly different threshold pattern, with the lowest thresholds at higher frequencies (ANOVA, *p < 0.01). Aging affected both strains similarly with near parallel upward threshold shifts. For the FBN strains, age-related threshold shifts did not correlate with the apical pattern of hair cell loss. Adapted from Turner and Caspary, 2005.

Fig. 3

The effects of aging on protein levels of GABA_A receptor subunit α₁, β₂ and γ₁ in the IC of FBN and F344 rats. The y-axis represents subunit protein percentage difference from young adult animals (3–4mos) of middle aged (18–20mos) and aged (28–32mos) in rat IC. Note that GABA_A receptor γ₁ subunit protein significantly increased in aged rats of both FBN and F344. While significantly decreased α₁ subunit protein was found in the IC of aged FBN rats, it was not found in aged F344 rats (*p < 0.05). Modified from Caspary et al., 1999.

Fig. 4

GABA (10nM - 10μM) modulation of ³[H]-TBOB binding in the CIC of young and aged F344 rats. The dose-response curve is shifted to the left. These data have functional implications since the aged GABA_A receptor must be more sensitive to GABA than the young GABA_A receptor for the channel to be open allowing TBOB to bind to the picrotoxin binding site. Modified from Milbrandt et al., 1996.

Fig. 5

FBN rat layer V neurons exhibit two major types of receptive field maps; (A) 32% showed the classic V/U-shape with young and aged neurons showing similar responses to current pulse stimulation (not shown). (B) 47% of pyramidal neurons demonstrated a more Complex, dynamic response map. Aged complex receptive field neurons responded more vigorously than young neurons to 200ms current pulses, suggesting altered inhibitory control. Such increased excitability to current would be consistent with reduced GAD₆₇ immunostaining around layer V (LV) somata (see insets, scale bar = 15 μm). Modified from Turner et al., 2005c.

Fig. 6

Age-related changes of GAD₆₇ message and protein levels in A1 and parietal cortex (PtA) of middle- and aged FBN rats compared to young adult rats. Significant age-related changes in GAD₆₇ message levels were seen across all layers of A1 in middle- and aged FBN rats (except layer IV of middle-aged A1). Significant GAD₆₇ message decreases within PtA occurred only in the aged group (A). Whereas all layers of middle-aged and aged A1 showed significant age-related decreases in GAD₆₇ protein, in PtA GAD₆₇ protein levels showed no age-related decreases except in layer IV of middle-aged and aged, and in middle-aged layer VI (B; *p < 0.05). Modified from Ling et al. 2005.