Significance of inhibitory recruitment in aging with preserved cognition: limiting gamma-aminobutyric acid type A α5 function produces memory impairment

Koh, Ming Teng; Branch, Audrey; Haberman, Rebecca P.; Gallagher, Michela

doi:10.1016/j.neurobiolaging.2020.02.019

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…A study of 21-month-old mice found a specific decrease in GABRA2 around neuronal cell bodies and proximal dendrites in the CA1 and CA3 (Palpagama et al, 2019). GABA A receptor activity is also correlated with cognitive performance in aged mice (Koh et al, 2013(Koh et al, , 2020. Exercise may induce an increase in GABRA2 in the aged hippocampus to compensate for an age-associated decline in inhibitory signaling, improving cognition in the process.…”

Section: Discussionmentioning

confidence: 99%

Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

Ionescu-Tucker

Butler

Berchtold

et al. 2021

Front. Aging Neurosci.

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Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3’s catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.

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Section: Discussionmentioning

confidence: 99%

Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

Ionescu-Tucker

Butler

Berchtold

et al. 2021

Front. Aging Neurosci.

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“…Postsynaptic inhibition is enhanced in granule cells in AU rats compared to AI rats (Tran et al, 2018, 2019), and somatostatin-positive HIPP interneurons are intact in AU rats but reduced in AI rats (Spiegel et al, 2013). Enhanced inhibition in granule cells in AU rats may support sparse coding in the DG, which is essential for pattern separation (Koh et al, 2020). With respect to the evidence that aging has a greater effect on the role of the pCA3-dCA1-LEC pathway compared to the dCA3-pCA1-MEC pathway, the loss of reelin expression in LEC neurons occurs in the condition of memory impairment in both AI rats and rhesus monkeys, with relative sparing of that condition in AU animals in both species (Long et al, 2020; Stranahan et al, 2011a, 2011b).…”

Section: Discussionmentioning

confidence: 99%

Loss of functional heterogeneity along the CA3 transverse axis in aging

Lee

Tilekeratne

Lukish

et al. 2021

Preprint

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Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. While the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, with proximal CA3 supporting pattern separation and distal CA3 supporting pattern completion. We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. When the environmental similarity was high (e.g., altered cues or altered environment shapes in the same room), Y and AU rats showed more orthogonalized representations in proximal CA3 than in distal CA3, consistent with prior studies showing a functional dissociation along the transverse axis of CA3. In contrast, AI rats showed less orthogonalization in proximal CA3 than Y and AU rats but showed more normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. When the environmental similarity was low (e.g., recordings were done in different rooms), representations in proximal and distal CA3 remapped in all rats, showing that AI rats are able to dissociate representations when inputs show greater dissimilarity. These results provide evidence that the aged-related bias towards pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis and, furthermore, that proximal CA3 is the primary locus of this age-related dysfunction in neural coding.

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“…This compensation presumably keeps the population activity level of hippocampal neurons in AU rats in the normal range displayed by YG rats. The upregulation of inhibition in AU rats is functionally significant as disrupting it impairs spatial memory (Koh et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Decreased investigatory head scanning during exploration in learning-impaired, aged rats

Rao

Lee

Gallagher

et al. 2021

Neurobiology of Aging

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Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats.However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the agedimpaired rats.

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Significance of inhibitory recruitment in aging with preserved cognition: limiting gamma-aminobutyric acid type A α5 function produces memory impairment

Cited by 17 publications

References 31 publications

Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

Loss of functional heterogeneity along the CA3 transverse axis in aging

Decreased investigatory head scanning during exploration in learning-impaired, aged rats

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