Insufficient augmentation of ambient GABA responsible for age-related cognitive deficit

Abstract

Age-related degeneration of intracortical inhibition could underlie declines in cognitive function during senescence. Based on a hypothesis that a decrease in basal concentration of ambient (extrasynaptic) GABA with aging leads to depressing intracortical inhibition, we investigated how the basal concentration affects stimulus-evoked activity (as signal), ongoing-spontaneous activity (as noise) of neurons and their (signal-to-noise) ratio S/N. We simulated a neural network model equipped with a GABA transport system that regulates ambient GABA concentration in a neuronal activity-dependent manner. An increase in basal concentration augmented ambient GABA, increased GABA-mediated inhibitory current, and depressed ongoing-spontaneous activity while still keeping stimulus-evoked activity. This led to S/N improvement, for which it was necessary for the reversal potential of GABA transporter to be close to the resting potential of neurons. Above the resting potential, ongoing-spontaneous activity was predominantly enhanced due to excessive GABA-uptake from the extracellular space by transporters. Below the resting potential, stimulus-evoked activity was predominantly depressed, caused by excessive GABA-release. We suggest that the insufficient augmentation of ambient GABA due to a decrease in its basal concentration may be one of the possible causes of cognitive deficit with aging, increasing ongoing-spontaneous neuronal activity as noise. GABA transporter may contribute to improving S/N, provided that its reversal potential is close to the resting potential.

GABA Levels in The Dorsal Anterior Cingulate Cortex Associated with Difficulty Ignoring Smoking-Related Cues in Tobacco-Dependent Volunteers

“…Despite the wealth of research suggesting prefrontal GABA has a role in cognition (Enomoto et al, 2011;Fujiwara et al, 2011;Paine et al, 2011;Pehrson et al, 2013;Rolls et al, 2008;Winterer and Weinberger, 2004), our results are correlative and thus we are unable to determine whether decreased dACC GABA/Cr directly causes enhanced attentional bias. Furthermore, we have not directly confirmed that GABA levels are stable during the time between the MRS scan and the Stroop task.…”

“…On a cellular level, GABA enhances neuronal communication by inhibiting inappropriate activation or 'noise' while allowing selective activation of task-relevant signals, thus facilitating optimal cognition (Paine et al, 2011;Rolls et al, 2008;Winterer and Weinberger, 2004). Although reduced prefrontal GABA is thought to partly explain cognitive deficits in schizophrenia (Enomoto et al, 2011;Paine et al, 2011;Rolls et al, 2008) and age-related cognitive decline (Fujiwara et al, 2011), the current findings suggest that lower levels of prefrontal GABA may account for cognitive interference by smoking cues in otherwise healthy, young smokers. Specifically, lower dACC GABA may reduce the ability to filter irrelevant information leading to distraction by salient stimuli such as smoking cues.…”

“…Reductions in dACC GABA/Cr may contribute to smoking cue attentional bias as mounting evidence indicates that low levels of prefrontal GABA contribute to attentional and cognitive dysfunction at a more basic level (Enomoto et al, 2011;Fujiwara et al, 2011;Paine et al, 2011;Pehrson et al, 2013). On a cellular level, GABA enhances neuronal communication by inhibiting inappropriate activation or 'noise' while allowing selective activation of task-relevant signals, thus facilitating optimal cognition (Paine et al, 2011;Rolls et al, 2008;Winterer and Weinberger, 2004).…”

“…In the present study, we focused on gamma-aminobutyric acid (GABA) concentrations in the dACC, as reduced prefrontal GABA has been associated with impaired cognition (Enomoto et al, 2011;Fujiwara et al, 2011;Paine et al, 2011) and addictive disorders (Behar et al, 1999;Ke et al, 2004;Levy and Degnan, 2012). Additionally, GABAergic agonists reduce cigarette consumption in clinical trials (Franklin et al, 2009), and disrupt reactivity to nicotine cues in preclinical studies (Paterson et al, 2005).…”

Growth Hormone–Releasing Hormone Effects on Brain γ-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging

“…42 In theoretical models, it has been suggested that deficits in GABA result in poorer performance because of an increase in background noise relative to stable stimulus strength, whereas supplementation overcomes this condition. 43 Consistent with this interpretation, reduced levels of dorsolateral prefrontal GABA in humans are related to greater impulsivity 44 and increased perseveration in schizophrenia. 45 …”