Medial septum modulates hippocampal gamma activity and prepulse inhibition in an N-methyl-d-aspartate receptor antagonist model of schizophrenia.

In an animal model of schizophrenia induced by NMDA receptor antagonists like phencyclidine, MK-801, and ketamine, the septohippocampal system plays a key role. These drugs cause behavioral and electrophysiological disruptions, including reduced prepulse inhibition of the acoustic startle response, hyperlocomotion, impaired auditory gating, and increased hippocampal gamma oscillations. A single hippocampal seizure produces similar effects. Inactivating or lesioning GABAergic neurons in the medial septum, deep brain stimulation of the medial septum or nucleus accumbens, or positive modulation of GABAB receptors can reduce these disruptions. The findings indicate a close link between high-amplitude hippocampal gamma oscillations and psychosis-relevant behaviors, suggesting the hippocampus acts as a hub in a brain network underlying these symptoms.

Study at a glance

Abstract

We reviewed the participation of the septohippocampal system in an animal model of schizophrenia that was acutely induced by systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist such as phencyclidine, MK-801 and ketamine. The NMDA receptor antagonist-induced model of schizophrenia is characterized by behavioral and electrophysiological disruptions, including a decrease in prepulse inhibition of the acoustic startle response (PPI), hyperlocomotion, decrease in gating of hippocampal auditory evoked potentials and robust increase in hippocampal gamma (30-100Hz) oscillations. Similar disruptions were also induced by a single electrographic seizure in the hippocampus. The behavioral and electrophysiological disruptions induced by an NMDA receptor antagonist can be reduced by inactivation or lesion of GABAergic neurons in the medial septum, deep brain stimulation of the medial septum or nucleus accumbens, or positive modulation of GABAB receptors. Our results suggest a close association between high-amplitude hippocampal gamma oscillations and psychosis-relevant behaviors including PPI loss, behavioral hyperactivity and loss in auditory gating. Abnormal electrophysiology suggests a disruption of somatic and apical dendritic inhibition in the hippocampus, resulting in distorted sensory integration, and impaired cognitive and memory processing. The hippocampus is suggested to be a hub in a brain network that participates in psychosis-relevant behaviors, through its direct projection to the nucleus accumbens, or through indirect connections via the entorhinal, cingulate and prefrontal cortices.