title: The GSK-3-inhibitor VP2.51 produces antidepressant effects associated with adult hippocampal neurogenesis.
abstract: Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that has been implicated in the mechanism of action of mood stabilizers. According to the neurogenic hypothesis of depression, newborn neurons in the adult dentate gyrus are required for the antidepressant effects of certain agents. We demonstrate that administration of the GSK-3 inhibitor VP2.51 (2.5 mg/kg ip, for 3.5 weeks) increases cell proliferation (pH3+cells), as well as the short- and long-term survival of newborn neurons (assessed by the 24 h survival of BrdU+and DCX+neurons), while significantly increasing the commitment of cells to the granule neuron lineage (Prox1 immunoreactivity). In parallel, VP2.51 induces a net antidepressant effect, as judged by the decrease in the immobility time in the forced swim test of naïve mice (non-stressed mice), as well as a therapeutic effect on previously stressed mice (Porsolt-induced stress). Interestingly, the morphological changes were found prominently in the ventral region of the hippocampus. We found that these effects are neurogenesis dependent by combining the antimitotic temozolomide (50 mg/kg ip) with the drug. Importantly VP2.51 did not provoke changes in weight or in a battery of behavioral tests (learning/memory and activity tests). As the effects of VP2.51 were concomitant with the increase in β-catenin expression and a shift towards the inactive form of GSK-3, we suggest that VP2.51 has therapeutic benefits following stress, and it may be a preventive treatment in situations where a potential depressive state and/or loss of memory is associated with diminished neurogenesis, through selective GSK3-beta inhibition.
authors.affiliation: Molecular, Cellular and Developmental Neurobiology Department, Cajal Institute-CSIC, 28002 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez-Domper
authors.affiliation: Instituto de Química Medica-CSIC, 28006 Madrid, Spain.
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.affiliation: Molecular, Cellular and Developmental Neurobiology Department, Cajal Institute-CSIC, 28002 Madrid, Spain.
authors.forename: Simona
authors.initials: S
authors.lastname: Gradari
authors.affiliation: Instituto de Química Medica-CSIC, 28006 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Molecular, Cellular and Developmental Neurobiology Department and CIBERNED, Cajal Institute-CSIC, 28002 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: de Ceballos
authors.affiliation: Centro de Investigaciones Biológicas-CSIC, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Molecular, Cellular and Developmental Neurobiology Department, Cajal Institute-CSIC, 28002 Madrid, Spain. Electronic address: jltrejo@cajal.csic.es.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Trejo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D050256:Antimitotic Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D013315:Stress, Psychological / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000077204:Temozolomide; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D050256:Antimitotic Agents; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D051176:beta Catenin; D003606:Dacarbazine; D038362:Glycogen Synthase Kinase 3; D000077204:Temozolomide
keywords: Adult hippocampal neurogenesis; Antidepressants; Depression; Forced swim test; GSK-3 inhibitor; Stress; Tail suspension test