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, 9 (3), 104-127

Novel Players in the Aging Synapse: Impact on Cognition


Novel Players in the Aging Synapse: Impact on Cognition

Mariana Temido-Ferreira et al. J Caffeine Adenosine Res.


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.

Keywords: NMDA receptor; adenosine A2A receptor; aging; hippocampus; mGluR5 receptor; memory; synaptic plasticity.

Conflict of interest statement

No competing financial interests exist.


<b>FIG. 1.</b>
FIG. 1.
Hippocampal anatomy and circuitry. (A) Principal anatomy of the human hippocampal memory systems and the brain regions involved in learning and memory. (B) Schematic rat brain with the hippocampal formation highlighted. (C) Schematic hippocampal slice. (D) Hippocampal slice with different areas and layers. (E) Schematic representation of the hippocampal trisynaptic circuit. First, granule neurons in the hippocampal dentate gyrus receive afferent inputs, via the performant path, from the layer II of the lateral and MEC. Next, granule neurons project to the CA3 pyramidal neurons via mossy fibers and, ultimately, CA1 neurons receive inputs from the CA3 by the Schaffer collaterals, by the contralateral hippocampus through associational/commissural fibers or direct inputs from the performant path. To close the hippocampal synaptic loop, CA1 pyramidal neurons project back to the EC. Ant, anterior thalamic nuclei; CA, cornu ammonis; CM, corpus mammillaris; DG, dentate gyrus; EC, entorhinal cortex; LEC, lateral entorhinal cortex; LPP, lateral performant pathway; MEC, medial entorhinal cortex; Med, medial thalamic nuclei; MPP, medial performant pathway; Mtt, mamillothalamic tract; SN, septal nucleus. Adapted from Lavenex and Amaral. Color images are available online.
<b>FIG. 2.</b>
FIG. 2.
Glutamatergic pre- and postsynaptic neurons are very distinct structurally and functionally. (A) Electron micrographs of the CA1 area of the hippocampus showing morphological differences between pre- and postsynaptic components. The presynaptic element is easily identified by the presence of neurotransmitter-containing vesicles, generally of relatively uniform size. These vesicles aggregate near a membrane specialization that can be identified as a thickening, reflecting the presence of membrane proteins necessary for exocytosis—“active zone.” On the postsynaptic side, there is also an increased density of the membrane—postsynaptic density, a relatively detergent-resistant structure containing glutamate receptors and associated macromolecules (image kindly provided by Andreia Pinto, IMM JLA). (B) Most abundant subunit composition of ionotropic receptors AMPA, NMDA, and kainate in the hippocampus. (C) Representative AMPAR and NMDAR excitatory postsynaptic currents measured in a rat CA1 hippocampal neuron at −70 and +40 mV. (D) Schematic diagram of a glutamatergic synapse. Calcium influx through activation of presynaptic VDCC drives docking of the glutamate vesicles to the membrane. Once released, glutamate acts on postsynaptic AMPA (sodium influx), NMDA (sodium and calcium influx), kainate (sodium influx), and metabotropic receptors; adapted from Hassel and Dingledine. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GluA, AMPA receptor subunit; GluK, kainate receptor subunit; GluN, NMDA receptor subunit; NMDA, N-methyl-d-aspartate; VDCC, voltage-dependent calcium channels. Color images are available online.
<b>FIG. 3.</b>
FIG. 3.
Morphological and synaptic alterations upon aging in the CA1 area of the hippocampus. (A) Morphological and electrophysiological impairments observed upon aging in CA1; increased VDCC and aberrant NMDA receptor function impair calcium homeostasis, further enhanced by a decrease in activity of calcium buffering proteins, driving alterations in gene regulation. (B) Examples of LTP and LTD time courses upon different stimulation protocols (TBS: 10 trains with 4 pulses at 100 Hz, separated by 200 mseconds; HFS: 4 trains of 100 pulses at 100 Hz, separated by 5 minutes; low-frequency stimulation: 3 trains of 1200 pulses at 2 Hz, separated by 10 minutes); representative traces of fEPSPs before (black) and 50–60 minutes after (gray, green) LTD or LTP induction in young and aged rats. *p < 0.05. CBPs, calcium-binding proteins; fEPSPs, field excitatory postsynaptic potentials; HFS, high-frequency stimulation; LFS, low-frequency stimulation; LTD, long-term depression; LTP, long-term potentiation; TBS, theta-burst stimulation. Color images are available online.
<b>FIG. 4.</b>
FIG. 4.
Adenosine A2AR, distributed heterogeneously throughout the body, have important physiological functions in neurons, astrocytes, and microglia. (A) A2AR are particularly expressed in the lungs, spleen, thymus, heart, blood vessels, muscle, and brain. (B) A2AR are highly expressed in the olfactory bulb and striatum, whereas in the neocortex and hippocampus, they are present at residual levels. (C) Exogenous A2AR activation induces a presynaptic enhancement of phasic GABAergic inputs from parvalbumin-expressing neurons to other GABAergic INs, driving disinhibition of PYR (green line), whereas A2AR activation in PYR, presynaptically located, enhances glutamatergic inputs to other glutamatergic neurons (green line); A2AR do not affect neither monosynaptic inhibitory inputs to excitatory neurons nor monosynaptic glutamatergic inputs to INs (black line). (D) A2AR, predominantly presynaptic, increase the release of glutamate in the hippocampus, possibly by inducing Ca2+ uptake and PKA-dependent Ca2+ currents through P-type Ca2+ channels in the presynaptic CA3 neurons that project onto the CA1 PYR. Postsynaptically, A2AR facilitates AMPAR-evoked currents via PKA and increases mGluR5-dependent NMDAR phosphorylation and NMDAR-responses in CA1. However, pre- or postsynaptic localization of A2AR and whether this is a direct or indirect interaction is lacking. In astrocytes, A2AR activation induces astrocytic proliferation and activation and decreases glutamate uptake by controlling the expression levels of glutamate transporters subtypes GLT-I and GLAST.,, Microglial A2AR drive proliferation and activation, process retraction and release of important immune mediators, particularly cyclooxygenase, PGE2, NO, and IL-1β. A2AR, A2A receptors; CA1 and CA3, cornu ammonis 1 and 3; CCK+, cholecystokinin-positive interneuron; COX2, cyclooxygenase 2; GABA, gamma-aminobutyric acid; IL-1β, interleukin-1β; IN, interneuron; NO, nitric oxide; PGE2, prostaglandin E2; PV+, parvalbumin-positive interneuron; PYR, pyramidal cell; SLM, stratum lacunosum-moleculare; SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Color images are available online.
<b>FIG. 5.</b>
FIG. 5.
The aging synapse: in the CA1 area of the hippocampus, A2AR increased levels are associated with postsynaptic impairments, such as a mGluR5-dependent NMDAR activation, possibly through Fyn Kinases. NMDAR aberrant activation and VDCC increased expression trigger an increase in Ca2+ influx. Associated with a dysfunction of CBPs, this mechanism shifts Ca2+-dependent induction mechanism, which explains the alterations observed in LTP and LTD upon aging. Ca2+ dyshomeostasis and the associated synaptic plasticity shift impair gene regulation, further exacerbating synaptic dysfunction. Color images are available online.

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