Prepulse inhibition (PPI) of the acoustic startle response (ASR) can be used as an operational measure for brain mechanisms that prevent disruption of ongoing stimulus processing routines by other stimuli and that thereby avoid behavioral interference. Deficient PPI has been observed in schizophrenics; therefore, much interest has been devoted to the understanding of the neural basis of PPI. This study investigated the role of the septohippocampal system in the modulation of PPI in rats. Stimulation of the medial septum by injection of the glutamate agonist kainate led to a profound disturbance of PPI and reduced the ASR amplitude. The PPI deficit induced by intraseptal kainate was attenuated by systemic or intrahippocampal administration of the acetylcholine antagonist scopolamine. Lesions of the medial septum, made by the neurotoxin AMPA, did not affect PPI. The present data indicate that activation of the septohippocampal system reduces PPI of the ASR, suggesting its role in sensorimotor gating.