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Lentivirally mediated GSK-3? silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.

ABSTRACT: Inhibition of glycogen synthase kinase-3 (GSK-3) by pharmacological tools can produce antidepressant-like effects in rodents. However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioural effects remain elusive. We studied the effects of bilateral intra-hippocampal injections of lentivirus-expressing short-hairpin (sh)RNA targeting GSK-3? on behavioural performance in mice subjected to chronic stress. Pre-injection of lentivirus-expressing GSK-3? shRNA into the hippocampal dentate gyrus significantly decreased immobility time in both forced swim and tail suspension tests, while the locomotor activity of these mice was unchanged. These results suggest that lentiviral GSK-3? shRNA injection induces antidepressant-like effects in chronically stressed mice. Under these conditions, the expression levels of GSK-3? were persistently and markedly reduced in the hippocampus following GSK-3? shRNA injection. To our knowledge, this is the first demonstration that a single injection of lentivirus-expressing GSK-3? shRNA in the hippocampal dentate gyrus of chronically stressed mice has antidepressant-like effects elicited by gene silencing.

SUBMITTER: Omata N

PROVIDER: S-EPMC3125712 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.

Omata Naoto N Chiu Chi-Tso CT Moya Pablo R PR Leng Yan Y Wang Zhifei Z Hunsberger Joshua G JG Leeds Peter P Chuang De-Maw DM

The international journal of neuropsychopharmacology 20100707 5

Inhibition of glycogen synthase kinase-3 (GSK-3) by pharmacological tools can produce antidepressant-like effects in rodents. However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioural effects remain elusive. We studied the effects of bilateral intra-hippocampal injections of lentivirus-expressing short-hairpin (sh)RNA targeting GSK-3β on behavioural performance in mice subjected to chronic stress. Pre-injection of lentivirus-expressing GSK-3β shRNA into the hippo ...[more]

PMID: 20604988

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Project description:The hippocampus is one of the most widely studied areas in the brain because of its important functional role in memory processing and learning, its remarkable neuronal cell plasticity, and its involvement in epilepsy, neurodegenerative diseases, and psychiatric disorders. The hippocampus is composed of distinct regions; the dentate gyrus, which comprises mainly granule neurons, and Ammon's horn, which comprises mainly pyramidal neurons, and the two regions are connected by both anatomic and functional circuits. Many different mRNAs and proteins are selectively expressed in the dentate gyrus, and the dentate gyrus is a site of adult neurogenesis; that is, new neurons are continually generated in the adult dentate gyrus. To investigate mRNA and protein expression specific to the dentate gyrus, laser capture microdissection is often used. This method has some limitations, however, such as the need for special apparatuses and complicated handling procedures. In this video-recorded protocol, we demonstrate a dissection technique for removing the dentate gyrus from adult mouse under a stereomicroscope. Dentate gyrus samples prepared using this technique are suitable for any assay, including transcriptomic, proteomic, and cell biology analyses. We confirmed that the dissected tissue is dentate gyrus by conducting real-time PCR of dentate gyrus-specific genes, tryptophan 2,3-dioxygenase (TDO2) and desmoplakin (Dsp), and Ammon's horn enriched genes, Meis-related gene 1b (Mrg1b) and TYRO3 protein tyrosine kinase 3 (Tyro3). The mRNA expressions of TDO2 and Dsp in the dentate gyrus samples were detected at obviously higher levels, whereas Mrg1b and Tyro3 were lower levels, than those in the Ammon's horn samples. To demonstrate the advantage of this method, we performed DNA microarray analysis using samples of whole hippocampus and dentate gyrus. The mRNA expression of TDO2 and Dsp, which are expressed selectively in the dentate gyrus, in the whole hippocampus of alpha-CaMKII+/- mice, exhibited 0.037 and 0.10-fold changes compared to that of wild-type mice, respectively. In the isolated dentate gyrus, however, these expressions exhibited 0.011 and 0.021-fold changes compared to that of wild-type mice, demonstrating that gene expression changes in dentate gyrus can be detected with greater sensitivity. Taken together, this convenient and accurate dissection technique can be reliably used for studies focused on the dentate gyrus.

Dataset Information

Lentivirally mediated GSK-3? silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.

Publications

Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice.

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