The role of the GluR−A (GluR1) AMPA receptor subunit in learning and memory
ABSTRACT 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).
- SourceAvailable from: Chen Zhang
[Show abstract] [Hide abstract]
- "The primary aim of this study, therefore, was to evaluate the effect of OLZ and HAL on hippocampal-dependent memorial deficits (e.g., spatial learning and memory, as well as spatial working memory) usually observed in schizophrenia (Hanlon et al., 2011; Henseler et al., 2009; Wood et al., 2002) and to investigate the underlying neuroplasticity mechanism behind this discrepancy. It is known that the expression of LTP in the hippocampus requires the GluR1 subunit of the AMPA subtype of glutamate receptor (Sanderson et al., 2008). Oh et al. (2006) reported that GluR1 Ser845 phosphorylation can prime AMPA receptors for LTP; thus, as a secondary aim, we quantified the effect of OLZ and HAL on the state of Ser845 phosphorylation of GluR1 in the hippocampus. "
ABSTRACT: Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.Schizophrenia Research 09/2014; 159(2-3). DOI:10.1016/j.schres.2014.07.054 · 4.43 Impact Factor
[Show abstract] [Hide abstract]
- "By PND 30-32 mice show hippocampus dependent and hippocampus independent deficits while hyper-locomotion cannot be clearly seen and no double dissociation is possible since the poorer cognitive abilities may, theoretically, affect investigation (Sanderson et al., 2008). "
ABSTRACT: A RAS-related class of small monomeric G proteins, the RAB GTPases, is emerging as of key biological importance in compartment specific directional control of vesicles formation, transport and fusion. Thanks to human genetic observation and to the consequent dedicated biochemical work, substantial progress has been made on the understanding of the role played by RAB GTPases and their effector proteins on neuronal development and the shaping of cognitive functions. This review is highlighting these initial elements to broaden the current scope of research on developmental cognitive deficits and take the point of view of RAB GTPases control on membrane transport in neurons and astrocytes.Neuroscience & Biobehavioral Reviews 01/2014; 46. DOI:10.1016/j.neubiorev.2013.12.009 · 10.28 Impact Factor
[Show abstract] [Hide abstract]
- "In a typical working memory procedure, the organism must hold information online for a short period of time in order to successfully complete a goal-oriented task, such as the spatial information connected to the location of a food reward that enables maze navigation after a delay. The PFC (Goldman-Rakic, 1995) and the hippocampus (Sanderson et al., 2008) each participate in working memory function. Direct evidence demonstrating that these brain structures functionally interact during working memory has come from rodent experiments involving asymmetric pathway disconnection methods (also called ''crossed lesions''). "
ABSTRACT: While the hippocampal formation and the prefrontal cortex each have a well-established role in cognitive and mnemonic processes, the extent and manner in which these structures interact to achieve these functions has not been fully delineated. Recent research in rodents compellingly supports the idea that the projection of neurons extending from the CA1 region of the hippocampus and from the subiculum to the prefrontal cortex, referred to here as the H-PFC pathway, is critically involved in aspects of cognition related to executive function and to emotional regulation. Concurrently, it is becoming evident that persons suffering from schizophrenia, depression, and post-traumatic stress disorder display structural anomalies and aberrant functional coupling within the hippocampal-prefrontal circuit. Considering that these disorders involve varying degrees of cognitive impairment and emotional dysregulation, dysfunction in the H-PFC pathway might therefore be the common element of their pathophysiology. This overlap might also be intertwined with the pathway's evident susceptibility to stress and with its relationship to the amygdala. In consequence, the H-PFC pathway is a potentially crucial element of the pathophysiology of several psychiatric diseases, and it offers a specific target for therapeutic intervention, which is consistent with the recent emphasis on reframing psychiatric diseases in terms of brain circuits.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 01/2013; 23(10). DOI:10.1016/j.euroneuro.2012.10.018 · 5.40 Impact Factor