Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor

Corticosterone is known to suppress levels of 5-HTA(1A) receptor mRNA in rat hippocampus. We describe hippocampal 5-HT(1A) receptor mRNA regulation in mice that have a targeted disruption of the glucocorticoid receptor gene. 5-HT(1A) receptor mRNA levels as well as binding of [3H]8-OH-DPAT, were measured in the hippocampus of heterozygous and homozygous GR-deficient mice and in wild-type control mice. The effect of adrenalectomy in wild-type mice and heterozygous knockouts was also studied. We hypothesized that if the glucocorticoid receptor is important as a mediator of the suppressive effect of corticosterone, this would be revealed by changed (enhanced) expression of 5-HT(1A) receptor mRNA in mice with a genetically changed glucocorticoid receptor status. It was found that 5-HT(1A) receptor mRNA levels and 5-HT(1A) receptor binding were not different in GR-deficient mice. The 5-HT(1A) receptor mRNA levels were responsive to corticosterone, as adrenalectomy led to increased levels of hippocampal 5-HT(1A) receptor mRNA both in wild-type as in heterozygous knockout mice. These increases were paralleled by small but statistically significant changes in [3H]8-OH-DPAT binding. These results support a suppressive control of B over 5-HT(1A) receptor expression in the hippocampus of the mouse, which is predominantly mediated via the mineralocorticoid receptor. The data indicates that no interaction between the two corticosteroid receptors is required for this effect of corticosterone, and that mineralocorticoid receptor-mediated suppression of gene expression can take place in the complete absence of glucocorticoid receptor.     

Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats

Previously, a corticosterone surge associated with a learning task was shown to facilitate cognitive processes through brain glucocorticoid receptors (GR) while chronic overexposure to this stress hormone impaired cognition. In the present study we tested the hypothesis that opposing effects on learning and memory might also occur after either phasic or continuous blockade of brain GR by intracerebroventricular (i.c.v.) administration of the GR antagonist RU38486 (aGR). We used a Morris water maze procedure to assess spatial learning and memory abilities in male Wistar rats. The effect of phasic brain GR blockade was studied following daily pretraining administration of 10 and 100 ng/microL aGR i.c.v. on 3 consecutive days. This repetitive aGR treatment impaired spatial learning and memory dose-dependently in comparison with vehicle controls. For continuous brain GR blockade, animals received an i.c.v., infusion of aGR (10 and 100 ng/0.5 microL per h or vehicle) over 10 days. Infusion of 100 ng aGR per hour resulted in a long-lasting facilitation of spatial performance. The 10 ng aGR infusion also caused initially a facilitating effect, which was, however, transient and performance became impaired during retest. Possible anxiolytic properties of the drugs were excluded in view of the animals' behaviour in the elevated plus maze. Both doses of aGR infusion reduced the number of mineralocorticoid receptors in the hippocampus, but only the high dose of aGR resulted in a significant reduction of available GR sites. In conclusion, continuous administration of GR antagonist improves cognitive function, while phasic blockade of brain GR function causes a cognitive deficit.     

Impaired motor learning performance in cerebellar En-2 mutant mice.

Mice homozygous for a null mutation in their En-2 gene exhibit cerebellar neuroanatomical alterations including absence and misplacements of specific fissures and size reduction. The present study investigated cerebellar function by comparing the behavior of age-matched homozygous and heterozygous En-2 mutant and wild-type mice. Motor function of the mutants was found normal in several situations. Habituation to novelty in the open field was not significantly different in mutants. However, in a motor learning paradigm, the rotating rod, the performance of homozygous mutant mice improved significantly less than that of the heterozygous mice which were also significantly impaired compared to wild-type mice. Unlike other cerebellar mutants in which severe motor or sensory defects are obvious, the En-2 mouse model offers a unique tool to study the role of cerebellum in complex behavioral phenomena, including motor learning, without confounding effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor.

The glutamate analog, L-2-amino-4-phosphonobutyric acid (L-AP4) is a selective agonist for several members of the metabotropic glutamate receptor (mGluR) family. Activation of presynaptic mGluRs by L-AP4 causes a suppression of synaptic transmission in the central nervous system. In this study, the role of 1 subtype of mGluR in the nervous system was investigated by analyzing mutant mice lacking the L-AP4-sensitive receptor, mGluR4. Experiments designed to probe hippocampal function showed no impairments in acquisition of spatial learning in the water maze task. However, in a spatial reversal learning task, the mutant mice exhibited significantly accelerated learning performance. Furthermore, in a probe trial administered 6 weeks posttraining, these mice showed impaired spatial accuracy. The results suggest that the mutant mice differed in their ability to learn and integrate new spatial information into previously formed memory traces and that their use of stored spatial information also was altered. Thus, the presynaptically expressed mGluR4 plays a role in the processing of spatial information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory.

Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP

Class I metabotropic glutamate receptors (mGluRs) have been postulated to play a role in synaptic plasticity. To test the involvement of one member of this class, we have recently generated mutant mice that express no mGluR5 but normal levels of other glutamate receptors. The CNS revealed normal development of gross anatomical features. To examine synaptic functions we measured evoked field EPSPs in the hippocampal slice. Measures of presynaptic function, such as paired pulse facilitation in mutant CA1 neurons, were normal. The response of mutant CA1 neurons to low concentrations of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was missing, which suggests that mGluR5 may be the primary high affinity ACPD receptor in these neurons. Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the CA3 region, an NMDAR-independent pathway. Some of the difference in CA1 LTP could lie at the level of expression, because the reduction of LTP in the mutants was no longer observed 20 min after tetanus in the presence of 2-amino-5-phosphonopentanoate. We propose that mGluR5 plays a key regulatory role in NMDAR-dependent LTP. These mutant mice were also impaired in the acquisition and use of spatial information in both the Morris water maze and contextual information in the fear-conditioning test. This is consistent with the hypothesis that LTP in the CA1 region may underlie spatial learning and memory.     

Altered performance of reelin-receptor ApoER2 deficient mice on spatial tasks using the Barnes maze.

The apolipoprotein E receptor 2 (ApoER2), expressed predominantly in forebrain regions including the hippocampus, is 1 of 2 receptors for the extracellular matrix protein reelin, which is critical for cortical development. Previous studies of ApoER2 mutant mice have indicated deficits in synaptic plasticity and learning. The current authors assessed learning and memory of ApoER2 knockout and wild-type mice on the Barnes circular maze. Mice were trained in this task for 22 days, followed by memory recall and reversal tests. ApoER2 knockout mice were initially slower to complete the task, but by Day 22 they were more accurate than wild-type mice on several indices. There were no differences in memory assessed by the recall task, but ApoER2 knockout mice performed significantly worse on the memory reversal task. ApoER2 knockout mice also displayed altered use of specific search strategies and relationship of these strategies to errors made on the maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role and mechanisms of action of glucocorticoid involvement in memory storage

Adrenal steroid hormones modulate learning and memory processes by interacting with specific glucocorticoid receptors at different brain areas. In this article, certain components of the physiological response to stress elicited by learning situations are proposed to form an integral aspect of the neurobiological mechanism underlying memory formation. By reviewing the work carried out in different learning models in chicks (passive avoidance learning) and rats (spatial orientation in the Morris water maze and contextual fear conditioning), a role for brain corticosterone action through the glucocorticoid receptor type on the mechanisms of memory consolidation is hypothesized. Evidence is also presented to relate post-training corticosterone levels to the strength of memory storage. Finally, the possible molecular mechanisms that might mediate the influences of glucocorticoids in synaptic plasticity subserving long-term memory formation are considered, mainly by focusing on studies implicating a steroid action through (i) glutamatergic transmission and (ii) cell adhesion molecules.     

Acute blockade of hippocampal glucocorticoid receptors facilitates spatial learning in rats

Corticosteroids can facilitate or impair learning and memory processes. We found that the glucocorticoid receptor antagonist RU38486 injected locally into the dorsal hippocampus dose-dependently improved the performance of male Wistar rats in the water maze 24 h after treatment. This observation suggests a discrete specificity of hippocampal glucocorticoid receptors in facilitation of memory.     

Behavioural performance in three substrains of mouse strain 129

Recently, the possibility has been raised that the behavioural abnormalities seen in null-mutant mice might be determined by their genetic background rather than by loss of gene function, especially when the 129 mouse strain is used as supplier for embryonic stem (ES) cells. To examine this issue we tested three 129 mouse substrains (129/J, 129/Ola, 129/Sv-ter/+) and C57BL/6 (B6) in the Morris water maze, the open field, the plus maze and two tests assessing motor co-ordination. We identified only for the 129/J substrain substantial behavioural deficits. These mice are albinos and carry the pink-eyed dilution allele and differed in their basal anxiety level as assessed in the open-field test. They were severely impaired in spatial learning and memory (Morris water maze test), in the Porsolt swim test, which also measures learning and in motor co-ordination. However, the 129/J substrain has not been used as ES cell donor in null-mutant mice where behavioural abnormalities were observed. Instead, mice from 129/Ola and 129/Sv-ter/+ substrains have been commonly used as suppliers for ES cells. These performed normally in most of the tests, including Morris water maze test.     

Piracetam facilitates long-term memory for a passive avoidance task in chicks through a mechanism that requires a brain corticosteroid action

We investigated the effects of piracetam, a nootropic, on learning and memory formation for a passive avoidance task in day-old chicks. To test for the possible cognitive-enhancing properties of piracetam, a weak learning version of this task--whereby chicks maintain a memory to avoid pecking at a bead coated in a diluted aversant for up to 10 h--was used. Post-training (5, 30 or 60 min), but not pretraining, injections of piracetam (10 or 50 mg/kg, i.p.) increased recall for the task when the chicks were tested 24 h later. Because previous studies showed that long-term memory for the passive avoidance task is dependent upon a brain corticosteroid action, and because the efficacy of piracetam-like compounds is also modulated by corticosteroids, we tested whether the facilitating effect of piracetam was dependent upon a corticosteroid action through specific brain receptors (mineralocorticoid receptor and glucocorticoid receptor). First, increased plasma levels of corticosterone were found 5 min after piracetam injection. In addition, intracerebral administration of antagonists for each receptor type (RU28318, for mineralocorticoid receptors, and RU38486 for glucocorticoid receptors; i.c.) given before the nootropic inhibited the facilitative effect of piracetam on memory consolidation. These results give further support to a modulatory action of piracetam on the mechanisms involved in long-term memory formation through a neural action that, in this learning model, requires the activation of the two types of intracellular corticosteroid receptors.     

Null mutation of the prolactin receptor gene produces a defect in maternal behavior

We have studied pup-directed maternal behavior in mice carrying a germ line null mutation of the PRL receptor (PRLR) gene. Homozygous mutant and heterozygous mutant nulliparous females show a deficiency in pup-induced maternal behavior. Moreover, primiparous heterozygous females exhibit a profound deficit in maternal care when challenged with foster pups. Morris maze studies revealed normal configural learning in the heterozygous and homozygous animals. Eating, locomotor activity, sexual behavior, and exploration (all processes regulated by the hypothalamus) are normal in PRLR mutant mice. Olfactory function was tested in an aversive conditioning paradigm, results indicating that heterozygous and homozygous PRLR mutant mice are not anosmic. These studies clearly establish the PRLR as a regulator of maternal behavior.     

A role for the Ras signalling pathway in synaptic transmission and long-term memory

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.     

GluR-A-deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal.

Acquisition and reversal of a spatial discrimination were assessed in an appetitive, elevated plus-maze task in 4 groups of mice: knockout mice lacking the AMPA receptor subunit GluR-A (GluR1), wild-type controls, mice with cytotoxic hippocampal lesions, and controls that had undergone sham surgery. In agreement with previous studies using tasks such as the water maze, GluR-A-/- mice were unimpaired during acquisition of the spatial discrimination task, whereas performance in the hippocampal group remained at chance levels. In contrast to their performance during acquisition, the GluR-A-/- mice displayed a mild deficit during reversal of the spatial discrimination and were profoundly impaired during discrete trial, rewarded-alternation testing on the elevated T maze. The latter result suggests a short-term. flexible spatial working memory impairment in GluR-A-/- mice, which might also underlie their mild deficit during spatial reversal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.     

The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat.

Rats with bilateral N-methyl-D-aspartate lesions centered on the postrhinal cortex (POR) and sham lesions were tested in a series of spatial memory tasks. The POR-lesioned rats were significantly impaired compared with sham rats in the reference memory version of both the water maze and radial arm maze tasks and in the standard radial arm maze working memory task. The POR-lesioned rats displayed a delay-independent impairment in the working memory versions of the water maze and in a delayed nonmatching-to-place (DNMP) version of the radial arm maze task. The POR-lesioned rats were also impaired in a DNMP procedure conducted in the T-maze. These findings indicate that the POR has a delay-independent role in the processing of spatial information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice

Serotonin systems have been implicated in the regulation of hippocampal function. Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex. To assess the contribution of 5-HT2C receptors to the serotonergic regulation of hippocampal function, mice with a targeted 5-HT2C-receptor gene mutation were examined. An examination of long-term potentiation at each of four principal regions of the hippocampal formation revealed a selective impairment restricted to medial perforant path-dentate gyrus synapses of mutant mice. This deficit was accompanied by abnormal performance in behavioral assays associated with dentate gyrus function. 5-HT2C receptor mutants exhibited abnormal performance in the Morris water maze assay of spatial learning and reduced aversion to a novel environment. These deficits were selective and were not associated with a generalized learning deficit or with an impairment in the discrimination of spatial context. These results indicate that a genetic perturbation of serotonin receptor function can modulate dentate gyrus plasticity and that plasticity in this structure may contribute to neural mechanisms underlying hippocampus-dependent behaviors.     

Pharmacological evidence of the role of dorsal striatum in spatial memory consolidation in mice.

This study investigated the role of dorsal striatum in spatial memory in mice. The mice were tested for their ability to detect a spatial displacement 24 hrs after training. In order to manipulate the dorsal striatum, focal administrations of the N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5 phosphonopentanoic acid (AP-5) were performed immediately after training. AP-5 impaired the mice's ability to detect the spatial change only if their initial position was constant during training and testing. These findings demonstrate that NMDA receptor blockade within the dorsal striatum impairs spatial memory consolidation in a task in which no explicit reward or procedural learning is involved. The results are discussed with reference to a possible selective involvement of this structure in processing spatial information acquired through an egocentric, but not an allocentric, frame of reference. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversible Hippocampal Inactivation Partially Dissociates How and Where to Search in the Water Maze.

To assess the interaction between spatial and procedural memory systems, the authors developed a learning protocol in the water maze using a rising "Atlantis" platform that requires rats to learn to swim to a specific location and, once there, to learn a "dwelling" response to raise the platform. In this protocol, the effects of temporal inactivation of the dorsal hippocampus with the AMPA/kainate receptor antagonist LY326325 on different memory phases were investigated. Hippocampal inactivation impaired acquisition of the searching task, mainly because of disruption of procedural learning. Inactivation also impeded consolidation and retrieval of spatial information, while leaving expression of dwelling responses intact. These findings challenge the idea of a sharp demarcation between spatial and procedural learning with respect to hippocampal involvement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)