Dataset Information

Novel Players in the Aging Synapse: Impact on Cognition.

ABSTRACT: While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.

SUBMITTER: Temido-Ferreira M

PROVIDER: S-EPMC6761599 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Novel Players in the Aging Synapse: Impact on Cognition.

Temido-Ferreira Mariana M Coelho Joana E JE Pousinha Paula A PA Lopes Luísa V LV

Journal of caffeine and adenosine research 20190917 3

While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide ...[more]

PMID: 31559391

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Project description:ObjectiveThe impact of cognitive function and decline on political ideology is unknown. We studied the relationship between cognition and both political orientation and political policy choices in a population of older persons.DesignLongitudinal investigation.SettingA retirement community and its surroundings in Southern California.Participants151 members of a longitudinal investigation of aging and dementia in the oldest-old (the 90+ Study), mean age 95 years.MeasurementsParticipants self-reported their political ideology (7-point scale from extremely liberal to extremely conservative) and policy preferences for federal spending on public schooling, aid to the poor, and protecting the environment, as well as on preferences on immigration rates, death penalty, and university admission. The same political survey was mailed to participants twice: at time one and 6-months later. Cognitive function based on neurological examination and cognitive testing was classified as normal (55%), cognitive impairment/not dementia (CIND) (33%), or dementia (12%). We calculated rank correlations between ideology and policy choices, stratified by cognitive status, and agreement between Surveys 1 and 2.ResultsPolitical ideology/orientation was highly consistent over a six-month period (84% agreement) among the 122 who returned the second survey, with no significant relationship to cognitive status. Among cognitively impaired (CIND and dementia), however, there was significant loss of consistency between an individual's political orientation and their policy choices. Level of political engagement was high for participants, with more than 90% voting in the 2016 presidential election.ConclusionIn this population of older persons, political identification on the liberal-conservative spectrum was resilient despite cognitive decline, but its meaning and function were changed. For the cognitively impaired it remained a self-defining label, but no longer operated as a higher order framework for orienting specific policy preferences. There appeared to be loss of coherence between the political orientation and political policy choices of cognitively impaired individuals. Given the high level of political engagement of these individuals, these results have substantial public policy implications.

Project description:The lateral line (LL) is a sensory system that allows fish and amphibians to detect water currents. LL responsiveness is modulated by efferent neurons that aid in distinguishing between external and self-generated stimuli, maintaining sensitivity to relevant cues. One component of the efferent system is cholinergic, the activation of which inhibits afferent activity. LL hair cells (HCs) share structural, functional, and molecular similarities with those of the cochlea, making them a popular model for studying human hearing and balance disorders. Because of these commonalities, one could propose that the receptor at the LL efferent synapse is a α9α10 nicotinic acetylcholine receptor (nAChR). However, the identities of the molecular players underlying ACh-mediated inhibition in the LL remain unknown. Surprisingly, through the analysis of single-cell expression studies and in situ hybridization, we describe that α9, but not the α10, subunits are enriched in zebrafish HCs. Moreover, the heterologous expression of zebrafish α9 subunits indicates that homomeric receptors are functional and exhibit robust ACh-gated currents blocked by α-bungarotoxin and strychnine. In addition, in vivo Ca2+ imaging on mechanically stimulated zebrafish LL HCs show that ACh elicits a decrease in evoked Ca2+ signals, regardless of HC polarity. This effect is blocked by both α-bungarotoxin and apamin, indicating coupling of ACh-mediated effects to small-conductance Ca2+-activated potassium (SKs) channels. Our results indicate that an α9-containing (α9*) nAChR operates at the zebrafish LL efferent synapse. Moreover, the activation of α9* nAChRs most likely leads to LL HC hyperpolarization served by SK channels.SIGNIFICANCE STATEMENT The fish lateral line (LL) mechanosensory system shares structural, functional, and molecular similarities with those of the mammalian cochlea. Thus, it has become an accessible model for studying human hearing and balance disorders. However, the molecular players serving efferent control of LL hair cell (HC) activity have not been identified. Here we demonstrate that, different from the hearing organ of vertebrate species, a nicotinic acetylcholine receptor composed only of α9 subunits operates at the LL efferent synapse. Activation of α9-containing receptors leads to LL HC hyperpolarization because of the opening of small-conductance Ca2+-activated potassium channels. These results will further aid in the interpretation of data obtained from LL HCs as a model for cochlear HCs.

Dataset Information

Novel Players in the Aging Synapse: Impact on Cognition.

Publications

Novel Players in the Aging Synapse: Impact on Cognition.

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