Age-related changes in GABAA receptor subunit composition and function in rat auditory system

doi:10.1016/S0306-4522(99)00121-9

Neuroscience

Volume 93, Issue 1, June 1999, Pages 307-312

https://doi.org/10.1016/S0306-4522(99)00121-9 Get rights and content

Abstract

A decline in the ability to discriminate speech from noise due to age-related hearing loss (presbycusis) may reflect impaired auditory information processing within the central nervous system. Presbycusis may result, in part, from functional loss of the inhibitory neurotransmitter GABA. The present study assessed age-related changes of the GABA_A receptor in the inferior colliculus of young-adult, middle-aged, and aged rats related to: (i) receptor subunit composition and (ii) receptor function. Western blotting was used to measure protein levels of selected GABA_A receptor subunits in preparations obtained from the inferior colliculus of Fischer 344 and Fischer 344/Brown–Norway F1 hybrid rats. In both strains, the aged group exhibited significant increases in γ₁ subunit protein and a decrease in α₁ subunit protein. To examine the functional consequence of this putative age-related subunit change, we measured the ability of exogenous GABA to flux/translocate chloride ions into microsac preparations derived from Fischer 344 inferior colliculus. GABA-mediated chloride influx was significantly increased in samples prepared from the inferior colliculus of aged animals.

Together with previous studies, these results strongly suggest an age-related change in GABA_A receptor composition. These changes may reflect a compensatory up-regulation of inhibitory function in the face of significant loss of presynaptic GABA release. These findings provide one example of plastic neurotransmitter receptor changes which can occur during the ageing process.

Section snippets

Experimental procedures

Age-related changes in GABA_A receptor subunit protein content for the α₁, β_2/3, γ₁ and γ₂ subunits were measured using F344 (three, 18, 28 months) rats and FBN (four, 20, 32 months) rats. Due to inbreeding, pineal tumors and a shortened life span, the National Institute on Aging encouraged replacement of the F344 strain with the FBN F1 hybrid rat. Previous aging IC studies, including GABA_A subunit in situ hybridization,1., 6., 13., 23., 25., 29., 33. used F344 rats. For comparison, it was

GABA_A receptor subunit protein levels

In agreement with prior in situ hybridization studies (Fig. 2A, left-hand column),13., 25. quantitative densitometry of Western blots revealed a significant (P<0.05) age-related increase in γ₁ subunit protein for both strains. In the F344 rat (n=5 for all age groups), IC levels of γ₁ subunit protein in the aged group were significantly (P=0.05) increased to 52% above the young-adult group (Fig. 2A, center column). Age-wise comparison of γ₁ subunit protein levels in FBN (n=4 for all age groups)

Discussion

The age-related changes in subunit protein level observed in Western blots support the occurrence of an age-related change in GABA_A receptor subunit composition. The observed age-related increase in the percentage of γ₁ subunits in the GABA_A receptor complex appeared to result in an enhanced ability of IC microsacs to flux chloride in the presence of GABA. Alterations in the γ₁ subunit have been previously shown to alter the pharmacologic profile of the GABA_A receptor and the level of

Conclusion

A model based on the above literature and the present study demonstrates how age-related increases in the γ₁ and the α₂ subunit would increase GABA efficacy in the aged IC, perhaps as partial compensation for age-related presynaptic reductions in GABA release (Fig. 4). Since IC single neuron recording studies have shown age-related changes in response properties linked to GABA inhibition in response to acoustic stimulation,²⁹ it is unlikely that the observed receptor changes fully offset the

Acknowledgements

The authors thank Dr Vickram Ramkumar, Teresa Sommer, and Marty Wilson for their assistance with Western Blotting techniques, and Drs Richard Olsen, Robert Helfert and Ron Browning for their comments on the manuscript. Research supported by NIDCD grant No. DC00151.

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Age-related changes in GABAA receptor subunit composition and function in rat auditory system

Abstract

Section snippets

Experimental procedures

GABAA receptor subunit protein levels

Discussion

Conclusion

Acknowledgements

Changes with aging in the levels of amino acids in rat CNS structural elements II. Taurine and small neutral amino acids

Neurochem. Res.

Heterogeneous distribution of functionally important amino acids in brain areas of adult and aging humans

Neurochem. Res.

Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABA(A) receptor subunit expression

Neuron

Processing of interaural time and intensity differences in the cat inferior colliculus

Expl Brain. Res.

Central auditory aging: GABA changes in the inferior colliculus

Expl Gerontol.

Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: implications for neural presbycusis

J. Neurosci.

Auditory processes and aging: significant problems for research

Ear

γ-Aminobutyric acid gating of Cl− channels in recombinant GABAA receptors

J. Pharmac. exp. Ther.

Involvement of GABA in acoustically-evoked inhibition in inferior colliculus neurons

Hear. Res.

On the role of GABA as an inhibitory neurotransmitter in inferior colliculus neurons: iontophoretic studies

Brain Res.

Effects of excitant amino acids on acoustic responses of inferior colliculus neurons

Hear. Res.

Enhancement of GABA-activated membrane currents in aged Fischer 344 rat basal forebrain neurons

J. Neurosci.

Age-related decrease of GABAA receptor subunits and glutamic acid decarboxylase in the rat inferior colliculus

Neuroscience

GABAA receptor subunit expression changes in the rat cerebellum and cerebral cortex during aging

Molec. Brain Res.

Detectability index measures of binaural masking level difference across populations of inferior colliculus neurons

J. Neurosci.

Contribution of GABA- and glycine-mediated inhibition to the monaural temporal response properties of neurons in the inferior colliculus

J. Neurophysiol.

Native and recombinant GABAA receptor channels

Cell. Physiol. Biochem.

GABAA receptor channels

A. Rev. Neurosci.

Aging and neurotransmitter systems

Adv. biochem. Psychopharmac.

Age-related changes in GABA_A receptor subunit composition and function in rat auditory system

GABA_A receptor subunit protein levels

γ-Aminobutyric acid gating of Cl− channels in recombinant GABA_A receptors

Age-related decrease of GABA_A receptor subunits and glutamic acid decarboxylase in the rat inferior colliculus

GABA_A receptor subunit expression changes in the rat cerebellum and cerebral cortex during aging

Native and recombinant GABA_A receptor channels

GABA_A receptor channels