Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum

J Neurosci Res. 2002 Jun 1;68(5):511-21. doi: 10.1002/jnr.10256.


Brain-derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise-dependent gene upregulation of this neurotrophin. Focal lesions were produced by medial septal infusion of the saporin-linked immunotoxins 192-IgG-saporin or OX7-saporin. 192-IgG-saporin produced a selective and complete loss of medial septal cholinergic neurons with no accompanying GABA loss. Baseline BDNF mRNA was reduced in the hippocampus of sedentary animals, but exercise-induced gene upregulation was not impaired, despite complete loss of septo-hippocampal cholinergic afferents. OX7-saporin produced a graded lesion of the medial septum characterized by predominant GABA neuron loss with less reduction in the number of cholinergic cells. OX7-saporin lesion reduced baseline hippocampal BDNF mRNA and attenuated exercise-induced gene upregulation, in a dose-dependent manner. These results suggest that combined loss of septal GABAergic and cholinergic input to the hippocampus may be important for exercise-dependent BDNF gene regulation, while cholinergic activity on its own is not sufficient. These results are discussed in relation to their implications for aging and Alzheimer's disease.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / physiology
  • Acetylcholinesterase / analysis
  • Animals
  • Antibodies, Monoclonal / toxicity
  • Brain-Derived Neurotrophic Factor / genetics*
  • Choline O-Acetyltransferase / analysis
  • Cholinergic Agents / toxicity
  • Denervation
  • Gene Expression / physiology
  • Glutamate Decarboxylase / analysis
  • Hippocampus / physiology*
  • Immunoconjugates
  • Immunotoxins / toxicity
  • Male
  • N-Glycosyl Hydrolases
  • Neurons / enzymology
  • Neurons / pathology
  • Physical Exertion / physiology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Ribosome Inactivating Proteins, Type 1
  • Saporins
  • Septal Nuclei / pathology
  • Septal Nuclei / physiology*
  • gamma-Aminobutyric Acid / physiology


  • 192 IgG-saporin
  • Antibodies, Monoclonal
  • Brain-Derived Neurotrophic Factor
  • Cholinergic Agents
  • Immunoconjugates
  • Immunotoxins
  • OX7-saporin
  • RNA, Messenger
  • Ribosome Inactivating Proteins, Type 1
  • gamma-Aminobutyric Acid
  • Choline O-Acetyltransferase
  • Acetylcholinesterase
  • N-Glycosyl Hydrolases
  • Saporins
  • Glutamate Decarboxylase
  • Acetylcholine