GABAB receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats

McQuail, Joseph A.; Bañuelos, Cristina; LaSarge, Candi L.; Nicolle, Michelle M.; Bizon, Jennifer L.

doi:10.1016/j.neurobiolaging.2011.11.011

Cited by 34 publications

(47 citation statements)

References 52 publications

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“…In addition to GABA A Rs, expression of the GABA B R1 subunit is also reduced throughout the hippocampus of memory-impaired aged rats. Notably, however, lower expression of GABA B R1 is only accompanied by a reduction in GABA B R coupling to its effector G protein in CA3, suggesting that age-related GABA B R signaling dysfunction may be particularly pronounced in this hippocampal subregion [11,13]. Functional consequences for these age-related alterations in GABARs findings are illustrated by in vivo electrophysiological studies in which CA3 pyramidal neuron activity was monitored in behaving young and aged rats.…”

Section: Gabaergic Signaling Alterations In Aged Hippocampus and Impamentioning

confidence: 99%

“…Potentially in response to increased GABA availability, both the GABA B R1 and GABA B R2 subunits, which together form the functional GABA B R complex [90,91], are significantly reduced in the aged PFC, as is maximal baclofen-stimulated GTP exchange, a measure of GABA B R:G-protein coupling [11,14]. Notably, downregulation of GABA B Rs in aging might be expected to compensate for age-related elevations in extracellular GABA, thereby preserving an optimal level of excitation required for working memory (Box 2) [92].…”

Section: Gabaergic Signaling Alterations In Aged Prefrontal Cortex: Imentioning

confidence: 99%

“…The schematic shows representative presynaptic terminals from young adult and aged rat PFC that illustrate age-related changes in GABAergic signaling protein expression. Presynaptically, expression of glutamic acid decarboxylase (GAD) is upregulated in the aged PFC, and there is a concurrent reduction in expression of GABA transporter GAT-1 and GABA B R1a [11,14]. These changes suggest an imbalance in the capacity to produce GABA relative to the ability to clear synaptic GABA or inhibit its further release.…”

Section: Figurementioning

confidence: 99%

“…(A) Likely in response to excess GABA B R-mediated inhibition, expression of the subunits that together form postsynaptic GABA B Rs (GABA B R1b and GABA B R2) is reduced in the aged medial prefrontal cortex (mPFC) [11,14]. The downregulation of postsynaptic GABA B Rs receptor might serve to compensate for the excess inhibition described above as well as help to preserve the persistent activity of pyramidal neurons that is required for working memory maintenance.…”

Section: Figurementioning

confidence: 99%

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Molecular aspects of age-related cognitive decline: the role of GABA signaling

McQuail

Frazier

Bizon

2015

Trends in Molecular Medicine

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Alterations in inhibitory interneurons contribute to cognitive deficits associated with several psychiatric and neurological diseases. Phasic and tonic inhibition imparted by γ-amino-butyric acid (GABA) receptors regulates neural activity and helps to establish the appropriate network dynamics in cortical circuits that support normal cognition. This review highlights basic science demonstrating that inhibitory signaling is altered in aging, and discusses the impact of age-related shifts in inhibition on different forms of memory function, including hippocampus-dependent spatial reference memory and prefrontal cortex (PFU)-dependent working memory. The clinical appropriateness and tractability of select therapeutic candidates for cognitive aging that target receptors mediating inhibition are also discussed.

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Section: Gabaergic Signaling Alterations In Aged Hippocampus and Impamentioning

confidence: 99%

Section: Gabaergic Signaling Alterations In Aged Prefrontal Cortex: Imentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Molecular aspects of age-related cognitive decline: the role of GABA signaling

McQuail

Frazier

Bizon

2015

Trends in Molecular Medicine

Self Cite

163

123

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“…Alternatively, reduced principal cell activity in the aged PER could be due to enhanced inhibitory control. In fact, age-related imbalances between inhibition and excitation in the hippocampus (Yassa et al, 2011a;Spiegel et al, 2013;Thomé et al, 2016) and the prefrontal cortex (Insel et al, 2012;McQuail et al, 2012McQuail et al, , 2015Bañuelos et al, 2014;Beas et al, 2017) have been linked to impairments in spatial memory and executive functions, respectively. To date, however, limited data are available regarding whether age-related declines in PER principal cell activity results from enhanced inhibitory control versus reduced excitatory drive.…”

Section: Introductionmentioning

confidence: 99%

Attenuated Activity across Multiple Cell Types and Reduced Monosynaptic Connectivity in the Aged Perirhinal Cortex

et al. 2017

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The perirhinal cortex (PER), which is critical for associative memory and stimulus discrimination, has been described as a wall of inhibition between the neocortex and hippocampus. With advanced age, rats show deficits on PER-dependent behavioral tasks and fewer PER principal neurons are activated by stimuli, but the role of PER interneurons in these altered circuit properties in old age has not been characterized. In the present study, PER neurons were recorded while rats traversed a circular track bidirectionally in which the track was either empty or contained eight novel objects evenly spaced around the track. Putative interneurons were discriminated from principal cells based on the autocorrelogram, waveform parameters, and firing rate. While object modulation of interneuron firing was observed in both young and aged rats, PER interneurons recorded from old animals had lower firing rates compared with those from young animals. This difference could not be accounted for by differences in running speed, as the firing rates of PER interneurons did not show significant velocity modulation. Finally, in the aged rats, relative to young rats, there was a significant reduction in detected excitatory and inhibitory monosynaptic connections. Together these data suggest that with advanced age there may be reduced afferent drive from excitatory cells onto interneurons that may compromise the wall of inhibition between the hippocampus and cortex. This circuit dysfunction could erode the function of temporal lobe networks and ultimately contribute to cognitive aging.

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Age-Related Declines in Occipital GABA are Associated with Reduced Fluid Processing Ability

Simmonite

Carp²,

Foerster

et al. 2019

Academic Radiology

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Rationale and Objectives: Healthy aging is associated with pervasive declines in cognitive, motor, and sensory functioning. There are, however, substantial individual differences in behavioral performance among older adults. Several lines of animal research link age-related reductions of gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter, to age-related cognitive, motor, and sensory decline. Our study used proton magnetic resonance spectroscopy (MRS) at 3T to explore whether occipital GABA declines with age in humans and whether individual differences in occipital GABA are linked to individual differences in fluid processing ability. Materials and Methods: We used a MEGA-PRESS sequence that combines frequency spectral editing with a point-resolved spectroscopy sequence to quantify GABA. Spectra were obtained from a 30 × 30 × 25 mm voxel placed in the occipital cortex of 20 young adults (mean age 20.7 years) and 18 older adults (mean age 76.5 years). Participants also performed 11 fluid processing tasks outside the scanner, the results of which were z-scored and averaged to calculate a summary measure of fluid processing ability. Regression analysis was employed to determine the relationship between GABA concentrations in the occipital cortex and a summary measure of fluid processing ability. Results: Occipital GABA was significantly lower in older participants compared to the younger participants. We also observed a significant positive relationship between occipital GABA and fluid processing ability. In fact, higher GABA was associated with better task performance in 10 of the 11 tasks. Conclusion: These findings suggest that GABA levels decline with age in humans and are associated with declines in fluid processing ability.

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GABAB receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats

Cited by 34 publications

References 52 publications

Molecular aspects of age-related cognitive decline: the role of GABA signaling

Molecular aspects of age-related cognitive decline: the role of GABA signaling

Attenuated Activity across Multiple Cell Types and Reduced Monosynaptic Connectivity in the Aged Perirhinal Cortex

Age-Related Declines in Occipital GABA are Associated with Reduced Fluid Processing Ability

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