Neurological and psychiatric disorders are frequently associated with disruption 
of various cognitive functions, but development of effective drug treatments for 
these conditions has proven challenging. One of the main obstacles is the poor 
predictive validity of our preclinical animal models. In the present study the 
effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical 
in vivo electrophysiological models. Recently disclosed Phase III findings on 
semagacestat indicated that Alzheimer's disease (AD) patients on this drug 
showed significantly worsened cognitive function compared to those treated with 
placebo. Since previous studies have shown that drugs impairing cognitive 
function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor 
antagonists, and nociceptin receptor agonists) disrupt or decrease power of 
elicited theta oscillation in the hippocampus, we tested the effects of acute 
and sub-chronic administration of semagacestat in this assay. Field potentials 
were recorded across the hippocampal formation with NeuroNexus multi-site 
silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta 
oscillation was elicited by electrical stimulation of the brainstem nucleus 
pontis oralis. Sub-chronic administration of semagacestat twice daily over 12 
days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o. 
(per oral)] diminished power of elicited hippocampal theta oscillation. Acute, 
subcutaneous administration of semagacestat (100 mg/kg) produced a similar 
effect on hippocampal activity. We propose that the disruptive effect of 
semagacestat on hippocampal function could be one of the contributing mechanisms 
to its worsening of cognition in patients with AD. As it has been expected, both 
acute and sub-chronic administrations of semagacestat significantly decreased 
Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action 
of semagacestat in disrupting hippocampal oscillation.