Amyloid-β alters ongoing neuronal activity and excitability in the frontal cortex

Kellner, Vered; Menkes-Caspi, Noa; Beker, Shlomit; Stern, Edward A.

doi:10.1016/j.neurobiolaging.2014.04.001

Cited by 33 publications

(33 citation statements)

References 47 publications

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“…Furthermore, our observations are consistent with the evidence of increased metabolism and CBF at some point in the pathogenesis of AD that is later followed by a phase of reduced CBF (Ostergaard et al, 2013;Thambisetty et al, 2010). Hypermetabolism could be a compensatory mechanism (Elman et al, 2014) (Mormino et al, 2012) or simply an indicator of aberrant neuronal activity as a consequence of amyloid deposition (Kellner et al, 2014;Sperling et al, 2009). Conversely, abberant neuronal activity could promote amyloid deposition (Bero et al, 2011;Cirrito et al, 2005).…”

Section: Association Of Age With Epib As An Estimate Of Rcbf In Pibposupporting

confidence: 89%

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner

Gietl¹,

Warnock²,

Riese³

et al. 2015

Neurobiology of Aging

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Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

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Section: Association Of Age With Epib As An Estimate Of Rcbf In Pibposupporting

confidence: 89%

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner

Gietl¹,

Warnock²,

Riese³

et al. 2015

Neurobiology of Aging

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“…More importantly, A␤PP/PS1 mice treated with 9 -THC and CBD at advanced stages exhibit a reduction in GluR2/3 expression levels accompanied by an increase in the expression of GABA-A Rα1. These results suggest that natural cannabinoids alter the imbalance of excitatory versus inhibitory neural activity in the somatosensory cortex of aged A␤PP/PS1 mice [24,25]. In fact, A␤ has been demonstrated to inhibit long-term plasticity processes associated with learning and memory through suppression of CB 1 -dependent GABAergic synaptic disinhibition [26].…”

Section: Discussionmentioning

confidence: 86%

“…Thus, the reduction of GluR2/3 expression observed on treated mice might be the result of such depressed glutamatergic activity induced by chronic stimulation of CB 1 receptor. These modifications could contribute to counteract the alterations in neural excitability observed in A␤PP/PS1 mice [24,25] and in turn to improve cognitive performance. However, further experimental evidence will be needed to confirm the specific role of CB 1 receptors in such effects.…”

Section: Discussionmentioning

confidence: 99%

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

Aso

Andrés‐Benito

Ferrer

2016

JAD

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Abstract. Previous reports have demonstrated that the combination of 9 -tetrahydrocannabinol ( 9 -THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimerlike phenotype of A␤PP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in A␤PP/PS1 mice at advanced stages of the disease but are not effective in modifying the A␤ processing or in reducing the glial reactivity associated with aberrant A␤ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by 9 -THC and CBD in aged A␤PP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.

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“…Such structural changes suggest a shift in the normal balance of excitation and inhibition in this brain region that could be detrimental to cognitive capacities (Luebke et al, 2004; Stranahan et al, 2012; Bories et al, 2013; Baņuelos et al, 2014; McQuail et al, 2015). Indeed, cortical hyperexcitability has been suggested to underlie cognitive dysfunction across a variety of psychiatric and neurological diseases in which perseverative behaviors are prominent, including schizophrenia, Alzheimer’s disease, and autism (Volk and Lewis, 2002; Lewis et al, 2004; Hashimoto et al, 2008; Maldonado-Aviles et al, 2009; Enticott et al, 2010; Gonzalez-Burgos et al, 2011; Kellner et al, 2014; Silverman et al, 2015; Siwek et al, 2015). Consistent with reduced inhibition in the aged PFC, our laboratory has previously reported a marked decline in GABA(B) receptor expression in the aged mPFC (McQuail et al, 2012; Baņuelos et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats

et al. 2017

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The prefrontal cortex (PFC) is critical for the ability to flexibly adapt established patterns of behavior in response to a change in environmental contingencies. Impaired behavioral flexibility results in maladaptive strategies such as perseveration on response options that no longer produce a desired outcome. Pharmacological manipulations of prefrontal cortical GABAergic signaling modulate behavioral flexibility in animal models, and prefrontal cortical interneuron dysfunction is implicated in impaired behavioral flexibility that accompanies neuropsychiatric disease. As deficits in behavioral flexibility also emerge during the normal aging process, the goal of this study was to determine the role of GABAergic signaling, specifically via prefrontal cortical GABA(B) receptors, in such age-related deficits. Young and aged rats were trained in a set shifting task performed in operant chambers. First, rats learned to discriminate between two response levers to obtain a food reward on the basis of a cue light illuminated above the correct lever. Upon acquisition of this initial discrimination, the contingencies were shifted such that rats had to ignore the cue light and respond on the levers according to their left/right positions. Both young and aged rats acquired the initial discrimination similarly; however, aged rats were impaired relative to young following the set shift. Among aged rats, GABA(B) receptor expression in the medial prefrontal cortex (mPFC) was strongly correlated with set shifting, such that lower expression was associated with worse performance. Subsequent experiments showed that intra-mPFC administration of the GABA(B) receptor agonist baclofen enhanced set shifting performance in aged rats. These data directly link GABAergic signaling via GABA(B) receptors to impaired behavioral flexibility associated with normal aging.

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Amyloid-β alters ongoing neuronal activity and excitability in the frontal cortex

Cited by 33 publications

References 47 publications

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats

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