Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP

Matasha Dhar, Mingyan Zhu, Soren Impey, Talley J. Lambert, Tyler Bland, Ilia N. Karatsoreos, Takanobu Nakazawa, Suzanne M. Appleyard, Gary A. Wayman

Research output: Contribution to journalArticle

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Abstract

Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element-binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.

Original languageEnglish (US)
Pages (from-to)1073-1087
Number of pages15
JournalMolecular Endocrinology
Volume28
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Cyclic AMP Response Element-Binding Protein
Leptin
MicroRNAs
Leptin Receptors
Dendritic Spines
Spine
Pyramidal Cells
Mitogen-Activated Protein Kinase Kinases
Synapses
Cognition
Small Interfering RNA
Hypothalamus
Glutamic Acid
Hippocampus
Anxiety
Phosphorylation
Depression
Neurons

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology
  • Medicine(all)

Cite this

Dhar, M., Zhu, M., Impey, S., Lambert, T. J., Bland, T., Karatsoreos, I. N., ... Wayman, G. A. (2014). Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP. Molecular Endocrinology, 28(7), 1073-1087. https://doi.org/10.1210/me.2013-1332

Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP. / Dhar, Matasha; Zhu, Mingyan; Impey, Soren; Lambert, Talley J.; Bland, Tyler; Karatsoreos, Ilia N.; Nakazawa, Takanobu; Appleyard, Suzanne M.; Wayman, Gary A.

In: Molecular Endocrinology, Vol. 28, No. 7, 2014, p. 1073-1087.

Research output: Contribution to journalArticle

Dhar, M, Zhu, M, Impey, S, Lambert, TJ, Bland, T, Karatsoreos, IN, Nakazawa, T, Appleyard, SM & Wayman, GA 2014, 'Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP', Molecular Endocrinology, vol. 28, no. 7, pp. 1073-1087. https://doi.org/10.1210/me.2013-1332
Dhar, Matasha ; Zhu, Mingyan ; Impey, Soren ; Lambert, Talley J. ; Bland, Tyler ; Karatsoreos, Ilia N. ; Nakazawa, Takanobu ; Appleyard, Suzanne M. ; Wayman, Gary A. / Leptin induces hippocampal synaptogenesis via CREB-regulated MicroRNA-132 suppression of p250GAP. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 7. pp. 1073-1087.
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