Cognitive impairment and transmitter‐specific pre‐ and postsynaptic changes in the rat cerebral cortex during ageing

Majdi, Maryam; Ribeiro‐da‐Silva, Alfredo; Cuello, A. Claudio

doi:10.1111/j.1460-9568.2007.05966.x

Cited by 37 publications

(33 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the EPL, the ratio between symmetrical and asymmetrical synapses is also preserved, as well as the density of reciprocal synapses, supporting the hypothesis that D:D symmetrical and asymmetrical synapses are interdependent (31). Such balance between synapse types has also been reported in frontal and parietal cortices, where the ratio of excitatory to inhibitory synapses is maintained during the parallel decrease of both presynaptic boutons (34). However, maintenance of this balance is not a ubiquitous phenomenon, because inhibitory synapses are preferentially affected by the synapse reduction in the sensorimotor cortex (32).…”

Section: Discussionsupporting

confidence: 61%

Age-induced disruption of selective olfactory bulb synaptic circuits

Richard

Taylor²,

Greer³

2010

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

127

125

View full text Add to dashboard Cite

Little is known about how normal aging affects the brain. Recent evidence suggests that neuronal loss is not ubiquitous in aging neocortex. Instead, subtle and still controversial, region-and layerspecific alterations of neuron morphology and synapses are reported during aging, leading to the notion that discrete changes in neural circuitry may underlie age-related cognitive deficits. Although deficits in sensory function suggest that primary sensory cortices are affected by aging, our understanding of the age-related cellular and molecular changes is sparse. To assess the effect of aging on the organization of olfactory bulb (OB) circuitry, we carried out quantitative morphometric analyses in the mouse OB at 2, 6, 12, 18, and 24 mo. Our data establish that the volumes of the major OB layers do not change during aging. Parallel to this, we are unique in demonstrating that the stereotypic glomerular convergence of M72-GFP OSN axons in the OB is preserved during aging. We then provide unique evidence of the stability of projection neurons and interneurons subpopulations in the aging mouse OB, arguing against the notion of an age-dependent widespread loss of neurons. Finally, we show ultrastructurally a significant layer-specific loss of synapses; synaptic density is reduced in the glomerular layer but not the external plexiform layer, leading to an imbalance in OB circuitry. These results suggest that reduction of afferent synaptic input and local modulatory circuit synapses in OB glomeruli may contribute to specific age-related alterations of the olfactory function.aging | axodendritic synapses | dendrodendritic synapses | mitral cells A ge-related neurodegenerative diseases, such as Parkinson and Alzheimer's, involve localized or widespread neuronal loss, but little is known about the changes occurring in the brain during normal aging. A growing consensus argues against widespread neuronal loss and atrophy during aging (1, 2). Rather, subtle region-and layer-specific alterations of neuronal morphology and synaptic connections are reported in the neocortex and hippocampus, where they may contribute to age-related cognitive deficits.The laminar organization of olfactory bulb (OB) neurons and synapses provides a simplified cortical model in which we can probe principles of neuronal and synaptic organization during aging. Sensory functions are affected by aging, including alterations in olfactory acuity, discrimination, and memory (3-12). The OB is the first central relay in the pathway processing odor information: it receives afferent input from olfactory sensory neurons (OSNs) located in the olfactory epithelium (OE) and is responsible for detecting odors in the nasal cavity. OSN axons synapse on mitral/tufted cell dendrites in OB glomerular neuropils. OB local interneurons modulate the activity of mitral/tufted cells, contributing to odor signal integration, before propagation to the piriform cortex. Projections from the OE to the OB are organized in an odor receptor (OR) map; each subpopulation of OSNs expressin...

show abstract

Section: Discussionsupporting

confidence: 61%

Age-induced disruption of selective olfactory bulb synaptic circuits

Richard

Taylor²,

Greer³

2010

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

127

125

View full text Add to dashboard Cite

show abstract

“…For the count of TrkAimmunoreactive (IR) varicosities, size and shape criteria were applied to separate varicosities from axons. Confocal settings for acquisition and quantification were as previously described (Majdi et al, 2007;Allard et al, 2011). Differences between groups (vehicle vs treated) were analyzed using Student's t tests.…”

Section: Confocal Microscopy and Quantificationmentioning

confidence: 99%

Impact of the NGF Maturation and Degradation Pathway on the Cortical Cholinergic System Phenotype

Allard¹,

León²,

Pakavathkumar³

et al. 2012

J. Neurosci.

View full text Add to dashboard Cite

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.

show abstract

“…Therefore, cognitive decline could be a result of dysregulation of synaptic function and neurotransmission. Previous studies have reported age-related changes in glucose metabolism and long term potentiation as well as levels of neurotransmitters (dopamine, norepinephrine, 5-HT, GABA, acetylcholine) and trophic factors like brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factor-1 (Baxter et al, 1999; Foster, 2007; Gant et al, 2006; Gavilan et al, 2007; Hwang et al, 2006; Majdi et al, 2007; Mora et al, 2007; Rowe et al, 2007; Shi et al, 2007; Smith et al, 2000). Structural changes in the aging brain have also been demonstrated such as atrophy of various aspects of dendritic and synaptic morphology and vascular rarefaction (Dickstein et al, 2007; Shi et al 200; Sonntag et al 1997, 2000).…”

Section: Introductionmentioning

confidence: 99%

Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome

Sidhu¹,

Huang²,

Desai³

et al. 2016

Neurobiology of Aging

View full text Add to dashboard Cite

Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane (SPM) proteins supporting synaptic integrity and neurotransmission were down-regulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry (MS)-based protein quantitation combined with western blot or mRNA analysis. We found significant reduction of 15 SPM proteins in aging brains including fodrin-α, synaptopodin, PSD-95, SV2B, SNAP25, SNAP-α, NR2B, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, VAMP2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first nine proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins down-regulated during aging. Reduction of two of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function.

show abstract

Cognitive impairment and transmitter‐specific pre‐ and postsynaptic changes in the rat cerebral cortex during ageing

Cited by 37 publications

References 62 publications

Age-induced disruption of selective olfactory bulb synaptic circuits

Age-induced disruption of selective olfactory bulb synaptic circuits

Impact of the NGF Maturation and Degradation Pathway on the Cortical Cholinergic System Phenotype

Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome

Contact Info

Product

Resources

About