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GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats - PubMed

Comparative Study

GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats

Joseph A McQuail et al. Neurobiol Aging. 2012 Jun.

Abstract

Gamma aminobutyric acid (GABA)(B) receptors (GABA(B)Rs) have been linked to a wide range of physiological and cognitive processes and are of interest for treating a number of neurodegenerative and psychiatric disorders. As many of these diseases are associated with advanced age, it is important to understand how the normal aging process impacts GABA(B)R expression and signaling. Thus, we investigated GABA(B)R expression and function in the prefrontal cortex (PFC) and hippocampus of young and aged rats characterized in a spatial learning task. Baclofen-stimulated GTP-binding and GABA(B)R1 and GABA(B)R2 proteins were reduced in the prefrontal cortex of aged rats but these reductions were not associated with spatial learning abilities. In contrast, hippocampal GTP-binding was comparable between young and aged rats but reduced hippocampal GABA(B)R1 expression was observed in aged rats with spatial learning impairment. These data demonstrate marked regional differences in GABA(B)R complexes in the adult and aged brain and could have implications for both understanding the role of GABAergic processes in normal brain function and the development of putative interventions that target this system.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Disclosure/Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Spatial learning in young and aged rats

While young and aged rats improved as a function of training, aged rats were impaired relative to young at learning to swim to a hidden, submerged platform within the water maze [A]. Spatial learning index (SLI) scores (left y-axis) were greater, on average (noted by horizontal line), for aged rats than young indicating that aged rats were less proficient in searching for the platform location, however, the distribution of individual index scores demonstrates that aged rat performance spans a range which includes aged rats that are unimpaired relative to young (AU) and those exhibiting impaired performance (AI; greater than 2 standard deviations from young on right y-axis) [B]. When subgrouped according to SLI score, AI rats were significantly impaired on probe trial performance compared to young (Y) and age-matched controls without spatial learning impairment (AU) [C].

Figure 2
Figure 2. Baclofen-stimulated GTP-binding in the hippocampus of young and aged rats

Dose-response curves were not different between age groups [A] or cognitive groups [B]. The line of best-fit determined by non-linear, four-parameter fit is illustrated for young and aged rats.

Figure 3
Figure 3. Baclofen-stimulated GTP-binding in the prefrontal cortex of young and aged rats

Aged rats exhibited a 28% decrease in GTP-binding elicited by 1 mM baclofen in the prefrontal cortex [A] and this decrease was similar in aged-unimpaired (AU) and aged-impaired (AI) rats [B]. The line of best-fit determined by non-linear, four-parameter fit is illustrated for young and aged rats. * p<0.05 young versus aged.

Figure 4
Figure 4. GABABR1 and GABABR2 protein levels in hippocampus of young and aged rats

Levels of hippocampal GABABR1 isoforms were similar between age groups [A] but aged-impaired rats expressed less of both isoforms than young [B]. Levels of GABABR2 were not changed by age [C] or cognitive group [D]. Insets of A–D demonstrate representative immunoreactive bands observed for young and aged PFC samples when incubated with the indicated antibody. *p<0.05 versus young.

Figure 5
Figure 5. GABABR1 and GABABR2 protein levels in the prefrontal cortex of young and aged rats

Specific GABABR1 isoforms were similarly reduced by aging [A], but not differentially changed among cognitive groups [B]. Levels of GABABR2 are decreased by 32% in the aged PFC [C] irrespective of cognitive group [D]. Insets of A–D demonstrate representative immunoreactive bands observed for young and aged hippocampal samples when incubated with the indicated antibody. ** p<0.01 versus young.* p<0.05, ** p<0.01 versus young.

Figure 6
Figure 6. Ratios of GABABR1a:GABABR1b across PFC and hippocampus of young and aged rats

Relative levels of GABABR1a and GABABR1b were significantly different between the PFC and hippocampus (Hipp) when results from young and aged rats were pooled into a single analysis [A]. Relative expression ratios did not change as a function of age [B] or cognitive group [C]. Dashed line indicates a hypothetical value of 1 where the relative levels of expression of both isoforms are equivalent. *** p<0.001 PFC versus hippocampus.

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References

    1. Adams MM, Smith TD, Moga D, Gallagher M, Wang Y, Wolfe BB, Rapp PR, Morrison JH. Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats. J Comp Neurol. 2001;432:230–243. - PubMed
    1. Barense MD, Fox MT, Baxter MG. Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn Mem. 2002;9:191–201. - PMC - PubMed
    1. Baxter MG, Gallagher M. Neurobiological substrates of behavioral decline: Models and data analytic strategies for individual differences in aging. Neurobiol Aging. 1996;17:491–495. - PubMed
    1. Biermann B, Ivankova-Susankova K, Bradaia A, Abdel AS, Besseyrias V, Kapfhammer JP, Missler M, Gassmann M, Bettler B. The Sushi domains of GABAB receptors function as axonal targeting signals. J Neurosci. 2010;30:1385–1394. - PMC - PubMed
    1. Bizon JL, Helm KA, Han J, Chun H, Pucilowska J, Lund PK, Gallagher M. Hypothalamic–pituitary–adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged Long–Evans rats. European Journal of Neuroscience. 2001;14:1739–1751. - PubMed

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