Alterations in intrinsic neuronal excitability during normal aging

Disterhoft, John F.; Oh, M. Matthew

doi:10.1111/j.1474-9726.2007.00297.x

Cited by 121 publications

(119 citation statements)

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“…A common feature of brain aging is a decrease in synaptic strength or impaired communication between neurons (32,44,(55)(56)(57)(58). Synaptic connections become dysfunctional, perhaps in part as a result of reduced vesicle trafficking and neurotransmitter release, causing diminished plasticity (56,(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

180

103

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Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate agerelated cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.V itamin D, a secosteroid hormone known for its role in bone and calcium homeostasis, is now well recognized for its many diverse functions and actions on a variety of tissues and cell types (1, 2). Vitamin D typically refers to the precursor forms of the hormone obtained through the skin's exposure to sunlight [vitamin D3 (VitD3)] or from dietary sources (VitD3 or VitD2). A metabolite of vitamin D, 25-hydroxyvitamin D (25OHD), is a serum biomarker of vitamin D status or repletion. In recent years, there is particular concern that large segments of the population may have low levels of 25OHD, and therefore are vitamin D-deficient (3). Due to factors such as reduced intake, absorption, and decreased exposure to sunlight, aging adults (≥50 y of age) are especially susceptible (3-6). Notably, this predisposition for lower 25OHD levels in the elderly has been linked to higher risk for numerous age-related disorders, including cancer and metabolic and vascular diseases (7-10).Inadequate vitamin D status also correlates with a greater risk for cognitive decline in the elderly (4,(11)(12)(13)(14)(15), suggesting that optimal levels may promote healthy brain aging (16,17). Because the brain expresses vitamin D receptors (VDRs) and can synthesize the active form of the hormone, the possible cognitive enhancing effects of vitamin D may reflect a primary action in the brain rather than a result of secondary systemic effects (18)(19)(20)(21)(22). Indeed, we and others have shown that vitamin D, as ...

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Section: Discussionmentioning

confidence: 99%

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

180

103

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“…Disruption of neuronal excitability and abnormal AHP might contribute to neurodegeneration, in aging and AD brain (Ohno et al, 2004;Disterhoft and Oh, 2007;Driver et al, 2007;Ye et al, 2008). Transgenic mice overexpressing hAPPswe have an impairment of hippocampal gamma-frequency oscillations (Driver et al, 2007).…”

Section: Discussion Happ Expression In Rat Cortical Neurons Increasesmentioning

confidence: 99%

Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations

Santos¹,

Pierrot²,

Morel³

et al. 2009

J. Neurosci.

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Synchronous calcium oscillations are observed in primary cultures of rat cortical neurons when mature networks are formed. This spontaneous neuronal activity needs an accurate control of calcium homeostasis. Alteration of intraneuronal calcium concentration is described in many neurodegenerative disorders, including Alzheimer disease (AD). Although processing of amyloid precursor protein (APP) that generates A␤ peptide has critical implications for AD pathogenesis, the neuronal function of APP remains unclear. Here, we report that expression of human APP (hAPP) in rat cortical neurons increases L-type calcium currents, which stimulate SK channels, calcium-dependent K ϩ channels responsible for medium afterhyperpolarization (mAHP). In a neuronal network, increased mAHP in some neurons expressing hAPP leads to inhibition of calcium oscillations in all the cells of the network. This inhibition is independent of production and secretion of A␤ and other APP metabolites. In a neuronal network, reduction of endogenous APP expression using shRNA increases the frequency and reduces the amplitude of calcium oscillations. Altogether, these data support a key role for APP in the control of neuronal excitability.

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“…Furthermore, unlike cholinergic BF neurons, Ca 2ϩ buffering does not seem to be increased and may even be reduced with age in hippocampal CA1 neurons, given that Ca 2ϩ transients are increased in amplitude (Gant et al 2006;Hemond and Jaffe 2005;Thibault et al 2001) and addition of exogenous Ca 2ϩ buffers reverses hippocampal dysfunction and cognitive deficits (Ouanounou et al 1999;Tonkikh et al 2006). This reduced or unchanged Ca 2ϩ buffering and increased L-type Ca 2ϩ channel activity is believed to partially underlie an enhanced sAHP with age in CA1 neurons (Landfield and Pitler 1984;Power et al 2002) that alters the firing properties of these cells and contributes to cognitive impairment (reviewed in Disterhoft and Oh 2007). The sAHP is sensitive to the intracellular [Ca 2ϩ ] because it is mediated by a Ca 2ϩ -dependent K ϩ conductance (Sah 1996).…”

Section: Comparative Agingmentioning

confidence: 99%

Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

Murchison

McDermott

LaSarge

et al. 2009

Journal of Neurophysiology

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Murchison D, McDermott AN, LaSarge CL, Peebles KA, Bizon JL, Griffith WH. Enhanced calcium buffering in F344 rat cholinergic basal forebrain neurons is associated with age-related cognitive impairment. J Neurophysiol 102: 2194 -2207, 2009. First published August 12, 2009 doi:10.1152/jn.00301.2009. Alterations in neuronal Ca 2ϩ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca 2ϩ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca 2ϩ current recording with Ca 2ϩ -sensitive ratiometric microfluorimetry to measure Ca 2ϩ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age-or cognitionrelated changes in the amplitudes or fractional compositions of the whole cell Ca 2ϩ channel currents. However, Ca 2ϩ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca 2ϩ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca 2ϩ buffering by cholinergic basal forebrain neurons may be important during aging.

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Alterations in intrinsic neuronal excitability during normal aging

Cited by 121 publications

References 100 publications

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations

Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

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