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 disrupti on of finely tuned neuronal circuitry of discrete brain regions associ ated 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. Previou s efforts have mostly focused on direct effects on excitatory neurons. By contrast, less emphasis has been placed on addressing a role for t he intrinsic inhibitory component of cell-cell interactions of neurona l networks in response to A beta. The present study provides evidence demonstrating that blockage of the intrinsic inhibitory component betw een A beta exposed neurons leads to destabilization of calcium homeost asis and exacerbated neuronal death compared to A beta treated culture s. Neuronal electrical activity was first silenced by exposing culture s to tetrodotoxin (TTX; 100 nM) plus A beta, followed by survival coun ts. Cell death, unexpectedly, did not significantly differ from A beta -exposed neurons. The intrinsic inhibition in A beta-exposed cultures was then pharmacologically removed with picrotoxin (40 mu M) or bicucu lline (25 mu M) resulting in significantly greater death than A beta-e xposed neurons alone. From these observations, it is proposed that int rinsic functional inhibition in hippocampal circuits can reduce advers e effects of A beta on the excitatory component. By considering not ju st the excitatory component of electrical activity, but the intrinsic balance between excitation and inhibition, new strategies for the trea tment of Alzheimer disease may emerge. (C) 1998 Elsevier Science B.V.