The GABA–Working Memory Relationship in Alzheimer’s Disease (original) (raw)
Related papers
Frontal GABA Levels Change during Working Memory
PLoS ONE, 2012
Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing.
Frontiers in Behavioral Neuroscience, 2021
Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer’s disease (AD)—female sex and Apolipoprotein ε4 (ApoE ε4) genotype—on this relationship. Methods: Twenty healthy, community-dwelling individuals aged 50–71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education. Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001). Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.
GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease
Nature medicine, 2014
In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory [AU: in the mice?]. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
GABA A receptors in aging and Alzheimer’s disease
Journal of Neurochemistry, 2007
In this article we present a comprehensive review of relevant research and reports on the GABA A receptor in the aged and Alzheimer's disease (AD) brain. In comparison to glutamatergic and cholinergic systems, the GABAergic system is relatively spared in AD, but the precise mechanisms underlying differential vulnerability are not well understood. Using several methods, investigations demonstrate that despite resistance of the GABAergic system to neurodegeneration, particular subunits of the GABA A receptor are altered with age and AD, which can induce compensatory increases in GABA A receptor subunits within surrounding cells. We conclude that although aging-and disease-related changes in GABA A receptor subunits may be modest, the mechanisms that compensate for these changes may alter the pharmacokinetic and physiological properties of the receptor. It is therefore crucial to understand the subunit composition of individual GABA A receptors in the diseased brain when developing therapeutics that act at these receptors.
Reviews in The Neurosciences, 2016
Despite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer's disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.
ABSTRACTBackgroundγ-aminobutyric acid (GABA) is a primary inhibitory neurotransmitter that plays a significant role in the central nervous system. Studies on both animals and humans show it has the pharmacological potential for reducing the impact of cognitive disorders, as well as enhancing cognitive functions and mood. However, its specific effects on human attention and working memory have not yet been extensively studied.AimsIn this randomised, double-blind, placebo-controlled, and crossover trial, we aimed to test whether the administration of 800 mg GABA, dissolved in a drink, acutely affected visual working memory maintenance, as well as temporal and spatial attention in healthy adults.MethodsThe participants were 32 young adults (16 females and 16 males). Working memory recall precision, spatial attention and temporal attention were measured by a delayed match-to-sample task, a visual search task, and a speeded rapid serial visual presentation task, respectively. Participant...
GABA transporters (GAT-1) in Alzheimer's disease
Journal of Neural Transmission, 1999
The presynaptically located γ-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group of patients with Alzheimer's disease (AD) and in a control group using the GAT-1 selective radioligand [ 3 H]tiagabine. Post mortem brain tissue from frontal cortex, temporal cortex, and caudate nucleus from 18 AD patients and 23 age-matched controls were studied. The binding was saturable (Kd 26 nM) and region specific. There were no significant differences between the groups with respect to the binding capacity (Bmax) and binding affinity (Kd). The unaltered [ 3 H]tiagabine binding to GAT-1 protein indicates that intrinsic GABA neurons are spared in Alzheimer's disease.
Molecular Brain Research, 1998
Our work on the role of glutamate in Alzheimer's disease AD -related neuronal vulnerability and death provided significant insight Ž . into the potential contribution of the g-aminobutyric acid GABA neurotransmitter system as it participates in countering the neurotoxic effects of excessive glutamate receptor stimulation. Our previous studies demonstrate that b 2r3 GABA receptor subunit immuno-A reactivity is relatively well preserved in hippocampi with AD pathology. To further elucidate the molecular basis for this observation, we employed in situ hybridization histochemistry to examine the levels of b 2 and b 3 receptor subunit mRNAs in the hippocampus of 19 Ž . elderly subjects presenting with a broad range of pathologic severity i.e., Braak stage I-VI . Semi-quantitative analysis with film autoradiograms revealed that b 2 mRNA signal was highest in the granule cell layer, CA2 and CA1 subfields, while b 3 mRNA hybridization was highest in the granule cell layer, followed by CA2G CA3 G CA1 regions. No significant difference in b 2 mRNA expression was detected among the pathologically mild, moderate or severe groups. In contrast, levels of b 3 mRNA in the pathologically severe group was significantly decreased compared to the mild group within all subregions examined except CA4. Our data suggest that alterations in the expression of GABA receptor subunits in the AD hippocampus differ between specific receptor subunits with the A amount of b 2 mRNA being relatively well-preserved, while b 3 mRNA levels were decreased. q 1998 Elsevier Science B.V.
Polymorphic Genetic Markers of the GABA Catabolism Pathway in Alzheimer’s Disease
Journal of Alzheimer's Disease, 2020
Background: The compilation of a list of genetic modifiers in Alzheimer’s disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied. Objective/Methods: As an explorative study, we considered variants in genes of GABA catabolism (ABAT, ALDH5A1, AKR7A2), and APOE in 300 Italian patients and 299 controls. We introduce a recent multivariate method to take into account the individual APOE genotype, thus controlling for the effect of the discrepant allele distributions in cases versus controls. We add a genotype-phenotype analysis based on age at onset and the Mini-Mental State Evaluation score. Results: On the background of strongly divergent APOE allele distributions in AD versus controls, two genotypic interactions that represented a subtle but significant peculiarity of the AD cohort emerged. The first is between ABAT and APOE, and the second between some ALDH5A1 genotypes and APOE. Decreased S...