Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo

J Neurochem. 2004 Apr;89(2):324-36. doi: 10.1046/j.1471-4159.2004.02329.x.


Lithium has been demonstrated to increase neurogenesis in the dentate gyrus of rodent hippocampus. The present study was undertaken to investigate the effects of lithium on the proliferation and differentiation of rat neural progenitor cells in hippocampus both in vitro and in vivo. Lithium chloride (1-3 mM) produced a significant increase in the number of bromodeoxyuridine (BrdU)-positive cells in high-density cultures, but did not increase clonal size in low-density cultures. Lithium chloride at 1 mM (within the therapeutic range) also increased the number of cells double-labeled with BrdU antibody and TuJ1 (a class III beta-tubulin antibody) in high-density cultures and the number of TuJ1-positive cells in a clone of low-density cultures, whereas it decreased the number of glial fibrillary acidic protein-positive cells in both cultures. These results suggest that lithium selectively increased differentiation of neuronal progenitors. These actions of lithium appeared to enhance a neuronal subtype, calbindin(D28k)-positive cells, and involved a phosphorylated extracellular signal-regulated kinase and phosphorylated cyclic AMP response element-binding protein-dependent pathway both in vitro and in vivo. These findings suggest that lithium in therapeutic amounts may elicit its beneficial effects via facilitation of neural progenitor differentiation toward a calbindin(D28k)-positive neuronal cell type.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / biosynthesis
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Bromodeoxyuridine
  • Calbindin 1
  • Calbindins
  • Cell Count
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cell Division / drug effects
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / physiology
  • Immunohistochemistry
  • Lithium / pharmacology*
  • Male
  • Microtubule-Associated Proteins / biosynthesis
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • S100 Calcium Binding Protein G / biosynthesis
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism


  • Antigens, Differentiation
  • Calb1 protein, rat
  • Calbindin 1
  • Calbindins
  • Cyclic AMP Response Element-Binding Protein
  • Microtubule-Associated Proteins
  • S100 Calcium Binding Protein G
  • Lithium
  • Mitogen-Activated Protein Kinases
  • Bromodeoxyuridine