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Articles, Behavioral/Cognitive

Prefrontal Cortical GABAergic Dysfunction Contributes to Age-Related Working Memory Impairment

Cristina Bañuelos, B. Sofia Beas, Joseph A. McQuail, Ryan J. Gilbert, Charles J. Frazier, Barry Setlow and Jennifer L. Bizon
Journal of Neuroscience 5 March 2014, 34 (10) 3457-3466; https://doi.org/10.1523/JNEUROSCI.5192-13.2014
Cristina Bañuelos
1Department of Neuroscience,
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B. Sofia Beas
1Department of Neuroscience,
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Joseph A. McQuail
1Department of Neuroscience,
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Ryan J. Gilbert
1Department of Neuroscience,
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Charles J. Frazier
4Department of Pharmacodynamics, University of Florida, Gainesville, Florida 32610
1Department of Neuroscience,
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Barry Setlow
2Department of Psychiatry,
1Department of Neuroscience,
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Jennifer L. Bizon
1Department of Neuroscience,
2Department of Psychiatry,
3McKnight Brain Institute, and
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Abstract

Working memory functions supported by the prefrontal cortex decline in normal aging. Disruption of corticolimbic GABAergic inhibitory circuits can impair working memory in young subjects; however, relatively little is known regarding how aging impacts prefrontal cortical GABAergic signaling and whether such changes contribute to cognitive deficits. The current study used a rat model to evaluate the effects of aging on expression of prefrontal GABAergic synaptic proteins in relation to working memory decline, and to test whether pharmacological manipulations of prefrontal GABAergic signaling can improve working memory abilities in aged subjects. Results indicate that in aged medial prefrontal cortex (mPFC), expression of the vesicular GABA transporter VGAT was unchanged; however, there was a significant increase in expression of the GABA synthesizing enzyme GAD67, and a significant decrease in the primary neuronal GABA transporter GAT-1 and in both subunits of the GABA(B) receptor (GABA(B)R). Expression of VGAT, GAD67, and GAT-1 was not associated with working memory ability. In contrast, among aged rats, GABA(B)R expression was significantly and negatively associated with working memory performance, such that lower GABA(B)R expression predicted better working memory. Subsequent experiments showed that systemic administration of a GABA(B)R antagonist, CGP55845, dose-dependently enhanced working memory in aged rats. This enhancing effect of systemic CGP55845 was reproduced by direct intra-mPFC administration. Together, these data suggest that age-related dysregulation of GABAergic signaling in prefrontal cortex may play a causal role in impaired working memory and that targeting GABA(B)Rs may provide therapeutic benefit for age-related impairments in executive functions.

  • aging
  • CGP55845
  • executive function
  • GABA(B) receptor
  • inhibition
  • prefrontal cortex
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The Journal of Neuroscience: 34 (10)
Journal of Neuroscience
Vol. 34, Issue 10
5 Mar 2014
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Prefrontal Cortical GABAergic Dysfunction Contributes to Age-Related Working Memory Impairment
Cristina Bañuelos, B. Sofia Beas, Joseph A. McQuail, Ryan J. Gilbert, Charles J. Frazier, Barry Setlow, Jennifer L. Bizon
Journal of Neuroscience 5 March 2014, 34 (10) 3457-3466; DOI: 10.1523/JNEUROSCI.5192-13.2014

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Prefrontal Cortical GABAergic Dysfunction Contributes to Age-Related Working Memory Impairment
Cristina Bañuelos, B. Sofia Beas, Joseph A. McQuail, Ryan J. Gilbert, Charles J. Frazier, Barry Setlow, Jennifer L. Bizon
Journal of Neuroscience 5 March 2014, 34 (10) 3457-3466; DOI: 10.1523/JNEUROSCI.5192-13.2014
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Keywords

  • aging
  • CGP55845
  • executive function
  • GABA(B) receptor
  • inhibition
  • prefrontal cortex

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