Metabotropic Glutamate Receptor 3 Is Downregulated and Its Expression Is Shifted From Neurons to Astrocytes in the Mouse Lateral Septum During the Postpartum Period

Zhao, Changjiu; Gammie, Stephen C.

doi:10.1369/0022155415578283

Cited by 10 publications

(10 citation statements)

References 80 publications

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“…Further, structural changes have been identified in the maternal brain (Leuner and Gould, 2010, Shams et al, 2012), but LS has not been a focus of research. In terms of general plasticity (e.g., expression changes, neurotransmitter changes), though, we and others have documented numerous changes in LS (Francis et al, 2000, Caughey et al, 2011, Curley et al, 2012, Zhao et al, 2012a, Eisinger et al, 2013b, Driessen et al, 2014a, Zhao and Gammie, 2014, 2015). Understanding how the miRNA alterations lead to specific neurodevelopmental events would need to be addressed in follow up studies.…”

Section: Discussionmentioning

confidence: 79%

MicroRNA expression is altered in lateral septum across reproductive stages

et al. 2016

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MicroRNAs (miRNAs) inhibit RNA targets and may contribute to postpartum CNS gene expression changes, although this has never been tested. In the present study, we directly evaluated miRNA levels using RNA sequencing during reproduction in female mice in lateral septum (LS). We found the reliable and robust changes of miRNAs away from the virgin stage at the three other stages, namely pregnant, day 1 postpartum, and day 8 postpartum. For a given miRNA that was significantly different from the virgin condition in more than one group, the direction of change was always the same. Overall, we identified 32 upregulated miRNAs and 25 downregulated miRNAs that were consistently different from the virgin state. ‘Arm switching’ occurs for miR-433-3 and miR-7b. Unexpectedly, a third of upregulated miRNAs (relative to virgin) were highly localized within the 12qF1 region of chromosome 12 that includes the Dlk1-Dio3 gene cluster implicated in stem cell and neuronal differentiation. Over 1500 genes were targeted by multiple upregulated miRNAs with about 100 genes targeted by 5 or more miRNAs. Over 1000 genes were targeted by multiple downregulated miRNAs with about 50 genes targeted by 5 or more miRNAs. Half of the target genes were regulated by up and downregulated miRNAs, indicating homeostatic regulation. Transcriptional regulation was the most enriched pathway for genes linked to up or down regulated miRNAs. Other enriched pathways included protein kinase activity (e.g., MAP kinase), CNS development, axon guidance, neurotrophin signaling, neuron development/differentiation, and neurogenesis. Previously published postpartum LS gene expression changes were enrichment for LS miRNA targets, as expected. Surprisingly, postpartum gene expression changes from other regions were also enriched against LS miRNA targets, suggesting a core group of miRNAs may act across the CNS during reproduction. Together, we directly examine miRNAs and find significant alterations in the postpartum brain.

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Section: Discussionmentioning

confidence: 79%

MicroRNA expression is altered in lateral septum across reproductive stages

et al. 2016

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“…These receptors were not assayed because our main hypothesis was based on presynaptic modulation of glutamatergic signaling. Also, LY379268 agonism of glial mGluR 3 has a separate function that induces production of neurotrophic factors [54] lasting 6–72-h post treatment [55, 56]. Although systemic administration of LY379268 is present in the brain at levels sufficient to activate mGluR 2 / 3 for at least 24-h post treatment [26], the 6-month off-treatment duration may have allowed the AD pathophysiology to resume in AβPP/PS1 mice a few days after LY379268 treatment was discontinued despite long-term modulation through postsynaptic and glial mechanisms.…”

Section: Discussionmentioning

confidence: 99%

LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in AβPP/PS1 Mice

Hascup

Britz

Findley

et al. 2019

JAD

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Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer's disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-Daspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated A␤PP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR) 2/3 agonist from 2-6 months of age when elevated glutamate levels are first observed but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of A␤PP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in A␤PP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in A␤PP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in A␤PP/PS1 was not observed.

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“…Finally, glutamate may modulate social play behavior in males via the activation of metabotropic glutamate receptors rather than ionotropic glutamate receptors. Subtypes of these G-protein coupled receptors are expressed in the LS and have been shown to be involved in social behavior (Mesic et al, 2015; Zhao & Gammie, 2015). Further studies are needed to prove the lack of involvement of glutamate in the regulation of male social play behavior.…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in extracellular release of GABA and glutamate in the lateral septum during social play behavior in juvenile rats: Implications for sex-specific regulation of social play behavior

Bredewold

Schiavo

Hart³

et al. 2015

Neuroscience

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Social play is a motivated and rewarding behavior that is displayed by nearly all mammals and peaks in the juvenile period. Moreover, social play is essential for the development of social skills and is impaired in social disorders like autism. We recently showed that the lateral septum (LS) is involved in the regulation of social play behavior in juvenile male and female rats. The LS is largely modulated by GABA and glutamate neurotransmission, but their role in social play behavior is unknown. Here, we determined whether social play behavior is associated with changes in the extracellular release of GABA and glutamate in the LS and to what extent such changes modulate social play behavior in male and female juvenile rats. Using intracerebral microdialysis in freely behaving rats, we found no sex difference in extracellular GABA concentrations, but extracellular glutamate concentrations are higher in males than in females under baseline condition and during social play. This resulted in a higher glutamate/GABA concentration ratio in males versus females and thus, an excitatory predominance in the LS of males. Furthermore, social play behavior in both sexes is associated with significant increases in extracellular release of GABA and glutamate in the LS. Pharmacological blockade of GABA-A receptors in the LS with bicuculline (100 ng/0.5 µl, 250 ng/0.5 µl) dose-dependently decreased the duration of social play behavior in both sexes. In contrast, pharmacological blockade of ionotropic glutamate receptors (NMDA and AMPA/kainate receptors) in the LS with AP-5 + CNQX (2 mM+0.4 mM/0.5 µl, 30 mM+3 mM/0.5 µl) dose-dependently decreased the duration of social play behavior in females, but did not alter social play behavior in males. Together, these data suggest a role for GABA neurotransmission in the LS in the regulation of juvenile social play behavior in both sexes, while glutamate neurotransmission in the LS is involved in the sex-specific regulation of juvenile social play behavior.

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Metabotropic Glutamate Receptor 3 Is Downregulated and Its Expression Is Shifted From Neurons to Astrocytes in the Mouse Lateral Septum During the Postpartum Period

Cited by 10 publications

References 80 publications

MicroRNA expression is altered in lateral septum across reproductive stages

MicroRNA expression is altered in lateral septum across reproductive stages

LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in AβPP/PS1 Mice

Dynamic changes in extracellular release of GABA and glutamate in the lateral septum during social play behavior in juvenile rats: Implications for sex-specific regulation of social play behavior

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