Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats

Abstract

SummaryThis study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT-1 and reduced glutamate uptake occur in the aged (24-27 months) SpragueDawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3-5 months) and aged rats are depressed by DL-TBOA, an inhibitor of glutamate transporter activity, in an N-Methyl-D-Aspartate (NMDA)-receptor-dependent manner. In aged but not in young rats, part of the depressing effect of DL-TBOA also involves metabotropic glutamate receptor (mGluRs) activation as it is significantly reduced by the specific mGluR antagonist d-methyl-4-carboxy-phenylglycine (MCPG). The paired-pulse facilitation ratio, a functional index of glutamate release, is reduced by MCPG in aged slices to a level comparable to that in young rats both under control conditions and after being enhanced by DL-TBOA. These results suggest that the age-associated glutamate uptake deficiency favors presynaptic mGluR activation that lowers glutamate release. In parallel, 2 Hz-induced long-term depression is significantly decreased in aged animals and is fully restored by MCPG. All these data indicate a facilitated activation of extrasynaptic NMDAR and mGluRs in aged rats, possibly because of an altered distribution of glutamate in the extrasynaptic space. This in turn affects synaptic transmission and plasticity within the aged hippocampal CA1 network.

Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering

“…The key mechanism of action of riluzole to prevent aging may well be the increase of glutamate uptake by glia transporters (19)(20)(21), correcting their decreased function that occurs with aging (14,16,17). Previous work has shown age-related partial rescue of a hippocampal glutamate transporter expression and spatial memory with riluzole treatment (15).…”

“…There is some evidence that astrocytic glutamate transporters decrease with aging (14, 15), and consequently reduce glutamate uptake (14,16,17). Reduced glutamate uptake can lead to glutamate spillover to the extrasynaptic space with electrophysiological repercussions (14).…”

“…There is some evidence that astrocytic glutamate transporters decrease with aging (14,15), and consequently reduce glutamate uptake (14,16,17). Reduced glutamate uptake can lead to glutamate spillover to the extrasynaptic space with electrophysiological repercussions (14). The potential use of glutamate modulators as a therapeutic target to regulate the synaptic age-related glutamatergic dysregulation in those vulnerable neural circuits remains to be further investigated.…”

Enhanced Asynchronous Ca2+ Oscillations Associated with Impaired Glutamate Transport in Cortical Astrocytes Expressing Fmr1 Gene Premutation Expansion

“…Moreover, astrocytes can influence neuronal connectivity by improper clearance of Glu from synaptic sites (51). Reduction in Glu uptake can stimulate extrasynaptic NMDA and metabotropic glutamate receptor activation at hippocampal CA1 synapses of aged rats (52). Therefore, impaired Glu uptake as well as a higher frequency of spontaneous Ca 2ϩ oscillations observed in preCGG astrocytes may contribute to neuropathological changes observed in premutation models and possibly to the etiology of FXTAS.…”

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

“…For example, aging, the greatest known risk factor for AD, is associated with a decline in glutamate transporters and uptake [173,174], leading to higher levels of extracellular glutamate [175]. This age-related increase in extracellular glutamate results in greater activation of extrasynaptic NMDARs [176,177] and could potentially be permissive for the spread of Aβ and tau pathology through vulnerable networks.…”