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Profile of changes in gene expression in cultured hippocampal neurones evoked by the GABAB receptor agonist baclofen.

ABSTRACT: Metabotropic gamma-aminobutyric acid receptors (GABA(B)Rs) play a critical role in inhibitory synaptic transmission in the hippocampus. However, little is known about a possible long-term effect requiring transcriptional changes. Here, using microarray technology and RT-PCR of RNA from cultured rat embryonic hippocampal neurones, we report the profile of genes that are up- or downregulated by activation of GABA(B)Rs by baclofen but are not changed by baclofen in the presence of the GABA(B)R antagonist CGP-55845A. Our data show, for the first time, regulation of transcription of defined mRNAs after specific GABA(B) receptor activation. The identified genes can be grouped into those encoding signal transduction, endocytosis/trafficking, and structural classes of proteins. For example, butyrylcholinesterase, brain-derived neurotrophic factor, and COPS5 (Jab1) genes were upregulated, whereas Rab8 interacting protein and Rho GTPase-activating protein 4 were downregulated. These results provide important baseline genomic data for future studies aimed at investigating the long-term effects of GABA(B)R activation in neurones such as their roles in neuronal growth, pathway formation and stabilization, and synaptic plasticity.

SUBMITTER: Ghorbel MT

PROVIDER: S-EPMC1563181 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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Profile of changes in gene expression in cultured hippocampal neurones evoked by the GABAB receptor agonist baclofen.

Ghorbel Mohamed T MT Becker Kevin G KG Henley Jeremy M JM

Physiological genomics 20050322 1

Metabotropic gamma-aminobutyric acid receptors (GABA(B)Rs) play a critical role in inhibitory synaptic transmission in the hippocampus. However, little is known about a possible long-term effect requiring transcriptional changes. Here, using microarray technology and RT-PCR of RNA from cultured rat embryonic hippocampal neurones, we report the profile of genes that are up- or downregulated by activation of GABA(B)Rs by baclofen but are not changed by baclofen in the presence of the GABA(B)R anta ...[more]

PMID: 15784695

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Project description:Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3beta-hydroxy (OH)-tibolone, which have oestrogenic effects, and the Delta 4-isomer (Delta 4-tibolone), which has progestogenic and androgenic effects. Because tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Using whole-cell patch clamp recording, we found previously that 17beta-oestradiol (E(2)) rapidly altered gamma-aminobutyric acid (GABA) neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E(2) reduced the potency of the GABA(B) receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K(+) (GIRK) channels in hypothalamic neurones. Therefore, we hypothesised that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone's action using selective inhibitors and whole cell recording in ovariectomised female guinea pigs and mice. A sub-population of neurones was identified post hoc as pro-opiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E(2), we have found that tibolone and its active metabolite 3 beta OH-tibolone rapidly reduced the potency of the GABA(B) receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182 780. Other metabolites of tibolone (3 alpha OH-tibolone and Delta 4-tibolone) had no effect. Furthermore, tibolone (and 3 beta OH-tibolone) was fully efficacious in ER alpha knockout (KO) and ER beta KO mice to attenuate GABA(B) responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E(2), the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3 beta OH-tibolone) activates phospholipase C leading to phosphatidylinositol bisphosphate metabolism and direct alteration of GIRK channel function. Therefore, tibolone may enhance synaptic efficacy through the G(q) signalling pathways of mER in brain circuits that are critical for maintaining homeostatic functions.

Dataset Information

Profile of changes in gene expression in cultured hippocampal neurones evoked by the GABAB receptor agonist baclofen.

Publications

Profile of changes in gene expression in cultured hippocampal neurones evoked by the GABAB receptor agonist baclofen.

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