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, UKProgress 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).
- "Of the many other genes within loci identified by the PGC, many are highly attractive and tractable drug targets, some of which have previously been the target of drug development programs. These include GRIN2A, which encodes the NMDA (N-methyl-daspartate ) receptor subunit NR2A, a key mediator of synaptic plasticity (Yashiro and Philpot, 2008), and GRIA1, which encodes glutamate receptor 1 (GluR1; also known as GluA1), an AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazo- lepropionic acid) receptor subunit that mediates fast synaptic transmission and is important for learning and memory (Sanderson et al., 2008). The PGC regions also contain SRR, which encodes serine racemase, an enzyme that catalyzes the conversion of L-serine to D-serine and is an essential co-agonist and activator of NMDA receptors (Campanini et al., 2013); CACNA1C, which encodes the alpha 1C subunit (Cav1.2) of the L-type voltage-gated calcium channel (Bhat et al., 2012); and CACNA1I, which encodes the pore-forming alpha subunit of the Cav3.3 "
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- "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    and AMPA activation is necessary for the consolidation/retention processes . NMDA receptors are important for triggering learning-related plasticity. "
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.
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- "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. "
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.
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