Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus

Abstract

In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca(2+) signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders.

Figure 1.

Neuroendocrine and behavioral effects of a single defeat session. A, Defeated mice show significantly increased corticosterone levels up to 8 h after onset of the stressor. B, In the spatial object recognition test, animals did not discriminate between the displaced and the nondisplaced object when stressed 8 h before. C, In the Y-maze, we found the same memory impairment as when animals were defeated 8 h before. D, Both control and defeated mice spent equal time sniffing in the female urine sniffing test 8 h after the defeat, indicating that there is no anhedonic behavior induced by a single defeat session. E, In the elevated plus maze, defeated animals show the same anxiety-related phenotype as their control littermates when tested 8 h after the stress. *p < 0.05; data are expressed as mean ± SEM.

Figure 2.

Homer1 mRNA level alterations in response to stress. A, After 4 and 8 h, Homer1b/c mRNA levels in the CA1 region are reduced. This reduction normalizes after 24 h. B, Representative autoradiographs of Homer1b/c mRNA levels in the hippocampus. C, Homer1a levels are not significantly altered in response to a single social defeat. One hour after onset of the stressor, an increase in Hoemr1a mRNA failed to reach significance (p = 0.077). D, Representative autoradiographs of Homer1a mRNA levels in the hippocampus. E, Interactions of mGluR5 and Homer1b/c are decreased 8 h after defeat stress. F, Representative Western blot of the mGluR5/Homer1 immunoprecipitation. For the technical control, a pooled lysate was incubated without primary antibodies. *p < 0.05, data are expressed as mean ± SEM.

Figure 3.

Manipulation of mGluR5/Homer1 but not glucocorticoid receptor signaling rescues cognitive impairments. A, A single injection of DEX (dexamethasone) that mimics a corticosterone response to a stressor was not able to induce changes in Homer1b/c mRNA levels. B, Eight hours after a single injection of DEX, experimental mice are not impaired in the Y-maze memory performance task. C, Mice that received a RU486 injection before the stressor are still affected by the defeat stress and cannot discriminate between the displaced and the nondisplaced object. D, Mice that received a MTEP injection before the stressor show functional learning behavior independent of the condition. *p < 0.05, data are expressed as mean ± SEM.

Figure 4.

Overexpression of Homer1b/c in the dorsal hippocampus rescues memory impairments induced by defeat stress. A, Homer1b/c mRNA levels in the dorsal hippocampus. Infection with the viral construct induced a robust increase. B, Representative autoradiographs of Homer1b/c mRNA levels in the dorsal and ventral hippocampus of control and Homer1 OE animals. C, Schematic representation of the extent of viral infection in the hippocampus from −1.44 to −2.72 mm posterior to bregma. Dark green, Strongest overexpression; light green, weaker overexpression. D, Visualization of Homer1b/c expression in the hippocampal DG region 5 weeks after injection of control (top panels) or Homer1b/c-expressing virus (bottom panels) (scale, 200 μm). E, Overexpression of Homer1b/c in the dorsal hippocampus prevents learning deficits induced by acute defeat stress. *p < 0.05, data are expressed as mean ± SEM.