The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory

School of Psychology, Cardiff University, Tower Building, Park Place, PO Box 901, Cardiff, CF10 3YG, UK
Progress in brain research (Impact Factor: 2.83). 04/2008; 169:159-178. DOI: 10.1016/S0079-6123(07)00009-X


It is widely believed that synaptic plasticity may provide the neural mechanism that underlies certain kinds of learning and memory in the mammalian brain. The expression of long-term potentiation (LTP) in the hippocampus, an experimental model of synaptic plasticity, requires the GluR-A subunit of the AMPA subtype of glutamate receptor. Genetically modified mice lacking the GluR-A subunit show normal acquisition of the standard, fixed-location, hidden-platform watermaze task, a spatial reference memory task that requires the hippocampus. In contrast, these mice are dramatically impaired on hippocampus-dependent, spatial working memory tasks, in which the spatial response of the animal is dependent on information in short-term memory. Taken together, these results argue for two distinct and independent spatial information processing mechanisms: (i) a GluR-A-independent associative learning mechanism through which a particular spatial response is gradually or incrementally strengthened, and which presumably underlies the acquisition of the classic watermaze paradigm and (ii) a GluR-A-dependent, non-associative, short-term memory trace which determines performance on spatial working memory tasks. These results are discussed in terms of Wagner's SOP model (1981).

22 Reads
  • Source
    • "Ionotropic glutamate receptors are required and well-studied in the context of learning and memory . Using genetic manipulation studies it was shown that AMPA subunit knockout animals show deficient spatial WM capabilities [11] [12] [13] and AMPA activation is necessary for the consolidation/retention processes [14]. NMDA receptors are important for triggering learning-related plasticity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several neurotransmitter receptors have been proposed to be involved in memory formation. However, information on receptor complexes (RCs) in the radial arm maze (RAM) is missing. It was therefore the aim of this study to determine major neurotransmitter RCs levels that are modulated by RAM training because receptors are known to work in homo-or heteromeric assemblies. Immediate early gene Arc expression was determined by immunohistochemistry to show if prefrontal cortices (PFC) and hippocampi were activated following RAM training as these regions are known to be mainly implicated in spatial memory. Twelve rats per group, trained and untrained in the twelve arm RAM were used, frontal cortices and hippocampi were taken, RCs in membrane protein were quantified by blue-native PAGE immunoblotting. RCs components were characterised by co-immunoprecipitation followed by mass spectrometrical analysis and by the use of the proximity ligation assay. Arc expression was significantly higher in PFC of trained as compared to untrained rats whereas it was comparable in hippocampi. Frontal cortical levels of RCs containing AMPA receptors GluA1, GluA2, NMDA receptors GluN1 and GluN2A, dopamine receptor D1, acetylcholine nicotinic receptor alpha 7 (nAChR-α7) and hippocampal levels of RCs containing D1, GluN1, GluN2B and nAChR-α7 were increased in the trained group; phosphorylated dopamine transporter levels were decreased in the trained group. D1 and GluN1 receptors were shown to be in the same complex. Taken together, distinct RCs were paralleling performance in the RAM which is relevant for interpretation of previous and design of future work on RCs in memory studies. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 04/2015; 289. DOI:10.1016/j.bbr.2015.04.043 · 3.03 Impact Factor
  • Source
    • "Thus, as demonstrated in hippocampal CA1 pyramidal cells, GLUA1- containing AMPA receptors are not critically involved in synaptic signal transmission, but they constitute a pool of extrasynaptic AMPA receptors that is necessary for activityinduced increases in synaptic transmission (Jensen et al, 2003; Zamanillo et al, 1999). Global GLUA1-deficient mice exhibit impairments in many different forms of learning and memory (for review see (Sanderson et al, 2008) as well as alterations in depressive and anxiety-like behaviors (Bannerman et al, 2004; Chourbaji et al, 2008c; Fitzgerald et al, 2010; Vekovischeva et al, 2004). Given the involvement of 5-HT in mood and anxiety, we hypothesised that these latter effects of the global Gria1 deletion involve changes in 5-HT function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1 encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that whilst α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.Neuropsychopharmacology accepted article preview online, 30 December 2014. doi:10.1038/npp.2014.332.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2014; 40(6). DOI:10.1038/npp.2014.332 · 7.05 Impact Factor
  • Source
    • "As GluA1 is required for the initiation of LTP (Sanderson et al., 2008), this putative mechanism provides one explanation for the deficits in dentate gyrus LTP observed in prenatal ethanol-exposed (Brady et al., 2013; Sutherland et al., 1997; Titterness & Christie, 2012; Varaschin et al., 2010) and prenatal stress-exposed (Titterness & Christie, 2012) offspring. Further, reductions in GluA subunit expression have been also associated with reduced performance on object recognition and passive avoidance tests (Schiapparelli et al., 2006), and animals lacking the GluA1 subunit have reduced performance on hippocampal-sensitive tasks such as radial arm maze and a non-matching to place T-maze, 2 measures of working memory (Sanderson et al., 2008). Clearly, additional work will be required to better elucidate the mechanistic basis for prenatal ethanol-induced and prenatal stressinduced deficits in synaptic plasticity and learning. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prenatal ethanol exposure and prenatal stress can each cause long-lasting deficits in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms underlying these perturbations following a learning event are still poorly understood. We examined the effects of prenatal ethanol exposure and prenatal stress exposure, either alone or in combination, on the cytosolic expression of activity-regulated cytoskeletal (ARC) protein and the synaptosomal expression of AMPA-glutamate receptor subunits (GluA1 and GluA2) in dentate gyrus of female adult offspring under baseline conditions and after 2-trial trace conditioning (TTTC). Surprisingly, baseline cytoplasmic ARC expression was significantly elevated in both prenatal treatment groups. In contrast, synaptosomal GluA1 receptor subunit expression was decreased in both prenatal treatment groups. GluA2 subunit expression was elevated in the prenatal stress group. TTTC did not alter ARC levels compared to an unpaired behavioral control (UPC) group in any of the 4 prenatal treatment groups. In contrast, TTTC significantly elevated both synaptosomal GluA1 and GluA2 subunit expression relative to the UPC group in control offspring, an effect that was not observed in any of the other 3 prenatal treatment groups. Given ARC’s role in regulating synaptosomal AMPA receptors, these results suggest that prenatal ethanol-induced or prenatal stress exposure-induced increases in baseline ARC levels could contribute to reductions in both baseline and activity-dependent changes in AMPA receptors in a manner that diminishes the role of AMPA receptors in dentate gyrus synaptic plasticity and hippocampal-sensitive learning.
    Alcohol 09/2014; 48(6). DOI:10.1016/j.alcohol.2014.06.006 · 2.01 Impact Factor
Show more