Inhibitory neuronal activity can compensate for adverse effects of β-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 β-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 A β. The present study provides evidence demonstrating that blockage of the intrinsic inhibitory component between A β exposed neurons leads to destabilization of calcium homeostasis and exacerbated neuronal death compared to A β treated cultures. Neuronal electrical activity was first silenced by exposing cultures to tetrodotoxin (TTX; 100 nM) plus A β, followed by survival counts. Cell death, unexpectedly, did not significantly differ from A β-exposed neurons. The intrinsic inhibition in A β-exposed cultures was then pharmacologically removed with picrotoxin (40 μM) or bicuculline (25 μM) resulting in significantly greater death than A β-exposed neurons alone. From these observations, it is proposed that intrinsic functional inhibition in hippocampal circuits can reduce adverse effects of A β 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.