title: Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory.
abstract: Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG.
  
  
  CONCLUSIONS
  In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an important role in adult hippocampal neurogenesis and spinogenesis. In addition, stathmin mutation led to impaired NMDA receptor-dependent and neurogenesis-associated memory and did not affect NMDA receptor-independent memory. Moreover, biochemical analysis suggested that stathmin regulates the synaptic transport of NMDA receptors, which in turn influence CREB-mediated gene transcription machinery. Overall, these data suggest that stathmin is an important molecule for neurogenesis, spinogenesis, and NMDA receptor-dependent learning and memory.
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854, Centre de Psychiatrie et Neurosciences, Inserm U894, 75014 Paris, France.
authors.forename: Guillaume
authors.identifier: http://orcid.org/0000-0002-2199-3772
authors.initials: G
authors.lastname: Martel
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854, Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Charles
authors.initials: C
authors.lastname: Hevi
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Itzamarie
authors.initials: I
authors.lastname: Chévere-Torres
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Ileana
authors.initials: I
authors.lastname: Fuentes
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Hannah
authors.initials: H
authors.lastname: Hafeez
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan, and.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan, and.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854, gleb@biology.rutgers.edu.
authors.forename: Gleb P
authors.initials: GP
authors.lastname: Shumyatsky
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology*; D004193:Discrimination Learning / Q000502:physiology; D000089622:Doublecortin Domain Proteins; D005106:Exploratory Behavior / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016194:Receptors, N-Methyl-D-Aspartate; D050797:STAT4 Transcription Factor; D019886:Gastrin-Releasing Peptide; D050882:CREB-Binding Protein
keywords: dentate gyrus; fear; hippocampus; memory; microtubules; stathmin
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