Aging Effects on the Limits and Stability of Long-Term Synaptic Potentiation and Depression in Rat Hippocampal Area CA1

Kumar, Ashok; Thinschmidt, Jeffrey S.; Foster, Thomas C.; King, Michael A.

doi:10.1152/jn.00249.2007

Cited by 64 publications

(64 citation statements)

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“…resonance imaging studies showed shrinking of hippocampal volume by 20% in elderly healthy adults [23]. Presented LTP measurements indicate the ability to induce and maintain synaptic plasticity in middleaged hippocampus in coincidence with finding even in senescent 22-24-m/o rats compared to young 1-12-m/o rats [24]. Pronounced reduction of absolute magnitude of fEPSP as well as fEPSP slope before and after HFS indicates persisting neurotransmission impairment already in the middle-aged rat hippocampus.…”

Section: Discussionsupporting

confidence: 73%

Middle-aged rat hippocampus and some early changes accompanying aging

Gaspárová

Janega²,

Prónayová

et al. 2012

Open Life Sciences

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Section: Discussionsupporting

confidence: 73%

Middle-aged rat hippocampus and some early changes accompanying aging

Gaspárová

Janega²,

Prónayová

et al. 2012

Open Life Sciences

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“…Consistent with this, we observed deficits in synaptic function before A␤ deposition that either corrected or stabilized as the animals aged and plaque formation began. Two potential explanations for this finding include a change in the toxic forms of A␤ at this age (Lesné et al, 2008) or an improved ability to compensate with age, perhaps due to age-dependent changes in the molecular mechanisms of LTP (Kumar et al, 2007;Gruart et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

Oral Treatment with a γ-Secretase Inhibitor Improves Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

Townsend

Gray

et al. 2010

J Pharmacol Exp Ther

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The ␤-amyloid peptide (A␤) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of A␤ on the brain, transgenic mouse models have been developed that express high levels of A␤. These mice show some features of AD, including amyloid plaques and mild cognitive impairment, but not others such as progressive neurodegeneration. We investigated the age-dependent effects of A␤ on synaptic physiology in Tg2576 mice that express human A␤. We report that both basal synaptic activity and long-term potentiation (LTP), as measured in the CA1 region of the hippocampus, were compromised by 7 months of age before plaque deposition. Despite a persistent increase in A␤ levels with age, LTP recovered in 14-month-old mice, with no further loss of basal activity compared with activity measured in 7-month-old mice. Previous work has shown that inhibitors of ␥-secretase, an enzyme critical for A␤ synthesis, can significantly reduce A␤ production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available ␥-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of A␤ reduction. These results indicate that recovery from A␤-mediated synaptotoxicity can occur rapidly with A␤-lowering therapies. These findings highlight some of the strengths and limitations of using A␤-overexpressing mouse models for Alzheimer's drug discovery.Alzheimer's disease (AD) is characterized clinically by progressive loss of memory and the pathological accumulation of neurofibrillary tangles and amyloid plaques in the brain. Tangles are composed of a fibrillized form of the microtubulebinding protein tau. Amyloid lesions contain ␤-amyloid peptide (A␤) produced endogenously by the proteolytic cleavage of the amyloid precursor protein (APP) by ␤-secretase and ␥-secretase (Wolfe, 2006;Cole and Vassar, 2008). Mutations near the cleavage sites of APP cause early onset AD as do variants in the ␥-secretase subunit presenilin 1. These mutations typically elevate A␤ production or increase A␤42/40 ratios, which result in a more aggregation-prone form of the peptide. Essential to developing disease-modifying therapies for AD is the identification and characterization of relevant preclinical animal models.Transgenic mice that express human disease variants of APP or presenilin 1 develop amyloid plaques, memory impairment, deficits in synaptic function, gliosis, and dystrophic neurites (Ashe, 2006; Gotz and Ittner, 2008;Morrissette et al., 2009). However, despite high levels of A␤ expression, these mice typically lack the overt tau pathology, neurodegeneration, and show only modest cognitive impairment. The full value of these preclinical models of Alzheimer's disease requires an explanation for the incomplete pathology. Tg2576 mice that express the APPsw mutation (K770N, M671L) have been widely studied (Hsiao et al., 1996;Ashe, 2006) as a model for pl...

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“…If further exploration of aging and AD changes in synaptic function and plasticity is one of your goals, there are at least two other methodological issues, alluded to above, that deserve further consideration. First, several labs have shown that the Ca 2+ :Mg2+ ratio in recording ACSF can have a marked effect on the induction synaptic plasticity in hippocampal slices 2,10,24,25 . In mammalian CSF, the Ca 2+ :Mg2+ ratio is approximately one (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Induction of LTD is particularly sensitive to subtle changes in ACSF Ca 2+ levels. Our protocol, which uses 2mM Ca 2+ and 2 mM Mg2+, commonly results in LTD for aged, but not young adult animals 2 , while studies using a Ca 2+ :Mg2+ ratio closer to two, have observed robust LTD in adults in the absence of an age difference 2,10 or in conjunction with reduced LTD in aged rats 32 . These observations highlight the need to carefully consider ACSF Ca 2+ and Mg2+ levels when comparing Ca…”

Section: +mentioning

confidence: 95%

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Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology

Mathis

Furman

Norris

2011

JoVE

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The rodent hippocampal slice preparation is perhaps the most broadly used tool for investigating mammalian synaptic function and plasticity. The hippocampus can be extracted quickly and easily from rats and mice and slices remain viable for hours in oxygenated artificial cerebrospinal fluid. Moreover, basic electrophysisologic techniques are easily applied to the investigation of synaptic function in hippocampal slices and have provided some of the best biomarkers for cognitive impairments. The hippocampal slice is especially popular for the study of synaptic plasticity mechanisms involved in learning and memory. Changes in the induction of long-term potentiation and depression (LTP and LTD) of synaptic efficacy in hippocampal slices (or lack thereof) are frequently used to describe the neurologic phenotype of cognitively-impaired animals and/ or to evaluate the mechanism of action of nootropic compounds. This article outlines the procedures we use for preparing hippocampal slices from rats and transgenic mice for the study of synaptic alterations associated with brain aging and Alzheimer's disease (AD) [1][2][3] . Use of aged rats and AD model mice can present a unique set of challenges to researchers accustomed to using younger rats and/or mice in their research. Aged rats have thicker skulls and tougher connective tissue than younger rats and mice, which can delay brain extraction and/or dissection and consequently negate or exaggerate real age-differences in synaptic function and plasticity. Aging and amyloid pathology may also exacerbate hippocampal damage sustained during the dissection procedure, again complicating any inferences drawn from physiologic assessment. Here, we discuss the steps taken during the dissection procedure to minimize these problems. Examples of synaptic responses acquired in "healthy" and "unhealthy" slices from rats and mice are provided, as well as representative synaptic plasticity experiments. The possible impact of other methodological factors on synaptic function in these animal models (e.g. recording solution components, stimulation parameters) are also discussed. While the focus of this article is on the use of aged rats and transgenic mice, novices to slice physiology should find enough detail here to get started on their own studies, using a variety of rodent models. Video LinkThe video component of this article can be found at https://www.jove.com/video/2330/ Protocol Preparing Ice-cold Oxygenated Artificial Cerebrospinal Fluid (ACSF)1. Prepare 2 L of "Ca 2+ -free" ACSF. In a 2L Erlenmeyer flask, add approximately 1.5 L of sterile or double-distilled H 2 O, and begin stirring vigorously on a stir plate. Add the following ACSF components (in mM): 124 NaCl, 2 KCl, 1.25 KH 2 PO 4 , 2 MgSO 4 , 26 NaHCO 3 , and 10 dextrose (see Table 1). Bring to a volume of 2 L with distilled H 2 O. 2. Using an aquarium bubbler and tubing attached to a 95% O 2 /5% CO 2 air tank, oxygenate ACSF vigorously for approximately 20-30 min.Check the pH, and if necessary, adjust to 7.4 using N...

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Aging Effects on the Limits and Stability of Long-Term Synaptic Potentiation and Depression in Rat Hippocampal Area CA1

Cited by 64 publications

References 64 publications

Middle-aged rat hippocampus and some early changes accompanying aging

Middle-aged rat hippocampus and some early changes accompanying aging

Oral Treatment with a γ-Secretase Inhibitor Improves Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology

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