Age-related loss of the GABA synthetic enzyme glutamic acid decarboxylase in rat primary auditory cortex

doi:10.1016/j.neuroscience.2004.12.043

Neuroscience

Volume 132, Issue 4, 2005, Pages 1103-1113

https://doi.org/10.1016/j.neuroscience.2004.12.043 Get rights and content

Abstract

Age-related changes within the auditory brainstem typically include alterations in inhibitory neurotransmission and coding mediated by GABA and glycinergic circuits. As part of an effort to evaluate the impact of aging on neurotransmission in the higher auditory centers, the present study examined age-related changes in the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in rat primary auditory cortex (AI), which contains a vast network of intrinsic and extrinsic GABAergic circuits throughout its layers. Message levels of the two GAD isoforms found in brain, GAD₆₅ and GAD₆₇, and GAD₆₇ protein levels were compared in young adult, middle-aged and aged rats using in situ hybridization and quantitative immunocytochemistry, respectively. For comparison, age-related GAD changes were also assessed in the parietal cortex and hippocampus.

Significant age-related decreases in GAD_65&67 messages were observed in AI layers II–VI of aged rats relative to their young adult cohorts. The largest changes were identified in layer II (GAD₆₅: −26.6% and GAD₆₇: −40.1%). GAD₆₇ protein expression decreased significantly in parallel with mRNA decreases in all layers of AI. Adjacent regions of parietal cortex showed no significant GAD₆₇ protein changes among the age groups, except in layer IV. As previously described, GAD₆₇ message and protein levels in selected hippocampal regions were significantly reduced in aged rats. Age-related GAD reductions likely reflect decreases in both metabolic and pre-synaptic GABA levels suggesting a plastic down-regulation of normal adult inhibitory GABA neurotransmission. Consistent with the present findings, functional studies in primate visual cortex and preliminary studies in AI find coding changes suggestive of altered inhibitory processing in aged animals. An age-related loss of normal adult GABA neurotransmission in AI would likely alter temporal coding properties and could contribute to the loss in speech understanding observed in the elderly.

Section snippets

Animals

Young adult (4–6 months), middle-aged (20–22 months) and aged (30–32 months) male FBN rats were obtained from Harlan Sprague-Dawley, Inc. (Indianapolis, IN, USA). All experiments were carried out under animal use protocols approved by the Southern Illinois University School of Medicine Laboratory Animal Care and Use Committee in consistent with the guidelines for the use of animals of IBRO and the Society for Neuroscience. All efforts were made to minimize the number of animals used and their

Results

All mRNA and protein measurements were obtained from single neurons irrespective of the number of neurons within AI, parietal cortex or hippocampus. Significant age-related decreases in GAD_65&67 mRNAs and GAD₆₇ protein were found in AI of middle-aged and aged rats relative to AI of young adult animals.

Discussion

The present findings are consistent with a hypothesis of an age-related down-regulation of GABAergic inhibition in AI. Significant age-related decreases in GAD_65&67 messages and GAD₆₇ protein were found across all AI layers. Recent neurochemical studies suggest that the pre-synaptic age-related down-regulation of GAD in FBN rat AI may be accompanied by a sequence of age-related post-synaptic GABA_A receptor subunit changes similar to those observed in IC (Milbrandt et al 1997, Caspary et al 1999

Acknowledgments

The authors thank Drs. Robert Helfert and Jeremy Turner for their comments on the manuscript. We also thank Judith Bryan and Jennifer Parrish for their helpful editing. This research is supported by NIH grant no. DC00151-25.

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Age-related loss of the GABA synthetic enzyme glutamic acid decarboxylase in rat primary auditory cortex

Abstract

Section snippets

Animals

Results

Discussion

Acknowledgments

Neurosci

Hear Res

Hear Res

Neurobiol Aging

Neuroscience

Exp Gerontol

Hear Res

Neuroscience

Neuron

Hear Res

Hear Res

Hear Res

Brain Res

Hear Res

Neurobiol Aging

Hear Res

Hear Res

Hear Res

Hear Res

Brain Res

Hear Res

Hear Res

Clin Neurophysiol

Hear Res

Activity-dependent regulation of glutamic acid decarboxylase in the rat barrel cortexeffects of neonatal versus adult sensory deprivation

J Comp Neurol

Changes with aging in the levels of amino acids in rat CNS structural elements: I. Glutamate and related amino acids

Neurochem Res

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

Presence of mRNA for glutamic acid decarboxylase in both excitatory and inhibitory neurons

Proc Natl Acad Sci USA

Age-related changes in the subunit makeup of the GABAA receptor in rat primary auditory cortex: GABAA receptors in cellular and network excitability: Orlando, FL. Poster B12

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

J Neurosci

Characterization of the protein purified with monoclonal antibodies to glutamic acid decarboxylase

J Neurosci

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNSevidence for anterograde axonal transport

J Neurosci

Effects of age and mild hearing loss on speech recognition in noise

J Acoust Soc Am

Paired-tone stimuli reveal reductions and alterations in temporal procession in inferior colliculus neurons of aged animals

J Assoc Res Otolaryn

Age effects on measures of auditory duration discrimination

J Speech Hear Res

Interneurons of the hippocampus

Hippocampus

Effects of whisker trimming on GABA(A) receptor binding in the barrel cortex of developing and adult rats

J Comp Neurol

Age-related changes in the subunit makeup of the GABA_A receptor in rat primary auditory cortex: GABA_A receptors in cellular and network excitability: Orlando, FL. Poster B12