Inhibitory neuronal activity can compensate for adverse effects of beta-amyloid in hippocampal neurons.
One of the most prominent effects of Alzheimer disease is the disruption of finely tuned neuronal circuitry of discrete brain regions associated with learning and memory. Results from the present study support a role for the intrinsic inhibitory component of neuronal circuitry in determining the magnitude of beta-amyloid peptide induced cell death in the highly vulnerable pyramidal neurons of the hippocampus. Previous efforts have mostly focused on direct effects on excitatory neurons. By contrast, less emphasis has been placed on addressing a role for the intrinsic inhibitory component of cell-cell interactions of neuronal networks in response to Abeta. The present study provides evidence demonstrating that blockage of the intrinsic inhibitory component between Abeta exposed neurons leads to destabilization of calcium homeostasis and exacerbated neuronal death compared to Abeta treated cultures. Neuronal electrical activity was first silenced by exposing cultures to tetrodotoxin (TTX; 100 nM) plus Abeta, followed by survival counts. Cell death, unexpectedly, did not significantly differ from Abeta-exposed neurons. The intrinsic inhibition in Abeta-exposed cultures was then pharmacologically removed with picrotoxin (40 microM) or bicuculline (25 microM) resulting in significantly greater death than Abeta-exposed neurons alone. From these observations, it is proposed that intrinsic functional inhibition in hippocampal circuits can reduce adverse effects of Abeta on the excitatory component. By considering not just the excitatory component of electrical activity, but the intrinsic balance between excitation and inhibition, new strategies for the treatment of Alzheimer disease may emerge.
Graf
R A
RA
Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523, USA.
Kater
S B
SB
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats / Q000196:embryology; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D001640:Bicuculline; D002118:Calcium; D018756:GABA Antagonists; D010852:Picrotoxin; D013779:Tetrodotoxin