Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.
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.
Berchtold
Nicole C
NC
Institute for Brain Aging and Dementia, University of California, Irvine, California, 92697-4540, USA. nberchto@uci.edu
Kesslak
J Patrick
JP
Cotman
Carl W
CW
D000109:Acetylcholine / Q000502:physiology; D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002795:Choline O-Acetyltransferase / Q000032:analysis; D018678:Cholinergic Agents / Q000633:toxicity; D003714:Denervation; D015870:Gene Expression / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000032:analysis; D006624:Hippocampus / Q000502:physiology*; D018796:Immunoconjugates; D000922:Immunotoxins / Q000633:toxicity; D008297:Male; D009699:N-Glycosyl Hydrolases; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D005082:Physical Exertion / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012686:Septal Nuclei / Q000473:pathology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D018678:Cholinergic Agents; D018796:Immunoconjugates; D000922:Immunotoxins; C085346:OX7-saporin; D012333:RNA, Messenger; D054789:Ribosome Inactivating Proteins, Type 1; D005680:gamma-Aminobutyric Acid; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D005968:Glutamate Decarboxylase; D000109:Acetylcholine