Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Steckler, Thomas; Weis, Carla; Sauvage, Magdalena; Mederer, Anna; Holsboer, Florian

doi:10.1016/s0166-4328(98)00115-6

Cited by 48 publications

(32 citation statements)

References 43 publications

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“…This resulted in a mouse expressing GR antisense mainly in neuronal tissue and this mutant was expected to be a well-suited animal model of depression associated with impaired GR function (Pepin et al 1992). This transgenic mouse was extensively studied and the main findings that emerged were the following: 1) these mice needed higher dexamethasone dosages than control mice in order to display corticosterone suppression under basal conditions or following CRH (Stec et al 1994); 2) CRH-elicited ACTH was higher in transgenic mice but corticosterone was lower in comparison to controls ; 3) these mice showed decreased corticosterone response to exogenous ACTH ); 4) when stressed, these mice showed increased ACTH levels, whereas corticosterone levels remain unchanged (Karanth et al 1997); 5) Dijkstra et al (1998) showed reduced activity of CRH neurons in the PVN of these mice and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced desensitisation; 6) these mice displayed an enhanced locomotorstimulating effect to morphine, a response that is reflected by an enhanced dopaminergic activity within the mesolimbic system (Spanagel et al 1996); 7) in these mice, responses to endotoxin were aberrant as noted by Linthorst and coworkers (1999), confirming that immune function is critically determined by appropriate GR function; 8) several studies (e.g., Montkowski et al 1995;Rousse et al 1997;Rochford et al 1997; showed that these mice have impairments in learning and memory paradigms which are also influenced by age; 9) Steckler et al (1999) concluded that allocentric spatial navigation is impaired whereas egocentric navigation is unimpaired. The latter authors suggested that the observed effects were due to hippocampal dysfunction secondary to GR deficiency and possible compensatory changes.…”

Section: Transgenic Mice Expressing Gr Antisensementioning

confidence: 71%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Transgenic Mice Expressing Gr Antisensementioning

confidence: 71%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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“…This points to coordinated MR-and GR-mediated actions on behavior. Therefore, it is of interest to know whether the mutation of GR affected the functionality of MR as was found previously in GR knockout and GR antisense mice (10,18) but also with continuous infusion of GR antagonist in rats (21). However, the presently observed similar explorative patterns of GR dim͞dim and control mice in the novel environments of the open field, the light͞dark box, and the first exposure to the pool (in the absence of a platform) point to a functional MR.…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, none of the parameters, which are related generally to anxiety, differed between the two groups. It is extremely important to monitor locomotion in connection with anxiety; increased locomotion as was observed in other mutant strains (10,18,19) may account for seemingly less anxious behavior when not controlled for.…”

Section: Discussionmentioning

confidence: 99%

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

Oitzl

Reichardt

Joëls

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

261

146

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Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding-dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GR dim͞dim ) while proteinprotein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light͞dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 g͞kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein-protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment.

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“…Initially, we examined hippocampus-dependent spatial learning in a well established discriminatory water-maze task (Arns et al, 1999;Steckler et al, 1999;Kleppisch et al, 2003), adapted from the paradigm originally described by Morris et al (1986b) for rats. This task has been proven to be hippocampus dependent using excitotoxic lesions (Arns et al, 1999).…”

Section: Ca1 Pyramidal Cells Inmentioning

confidence: 99%

Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Moosmang¹,

Haider²,

Klugbauer³

et al. 2005

J. Neurosci.

393

357

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Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of theCACNA1C(Cav1.2) gene in the hippocampus and neocortex (Cav1.2HCKO). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+influx to either process.

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Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Cited by 48 publications

References 43 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

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Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Cited by 48 publications

References 43 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

Role of Hippocampal Cav1.2 Ca2+Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

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Product

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Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory