Cholinergic Neurons of the Medial Septum Are Crucial for Sensorimotor Gating

Hypofunction of NMDA receptors has been considered a possible cause for the pathophysiology of schizophrenia. More recently, indirect ways to regulate NMDA that would be less disruptive have been proposed and metabotropic glutamate receptor subtype 5 (mGluR5) represents one such candidate. To characterize the cell populations involved, we demonstrated here that knock-out (KO) of mGluR5 in cholinergic, but not glutamatergic or parvalbumin (PV)-positive GABAergic, neurons reduced prepulse inhibition of the startle response (PPI) and enhanced sensitivity to MK801-induced locomotor activity. Inhibition of cholinergic neurons in the medial septum by DREADD (designer receptors exclusively activated by designer drugs) resulted in reduced PPI further demonstrating the importance of these neurons in sensorimotor gating. Volume imaging and quantification were used to compare PV and cholinergic cell distribution, density, and total cell counts in the different cell-type-specific KO lines. Electrophysiological studies showed reduced NMDA receptor-mediated currents in cholinergic neurons of the medial septum in mGluR5 KO mice. These results obtained from male and female mice indicate that cholinergic neurons in the medial septum represent a key cell type involved in sensorimotor gating and are relevant to pathologies associated with disrupted sensorimotor gating such as schizophrenia.SIGNIFICANCE STATEMENT The mechanistic complexity underlying psychiatric disorders remains a major challenge that is hindering the drug discovery process. Here, we generated genetically modified mouse lines to better characterize the involvement of the receptor mGluR5 in the fine-tuning of NMDA receptors, specifically in the context of sensorimotor gating. We evaluated the importance of knocking-out mGluR5 in three different cell types in two brain regions and performed different sets of experiments including behavioral testing and electrophysiological recordings. We demonstrated that cholinergic neurons in the medial septum represent a key cell-type involved in sensorimotor gating. We are proposing that pathologies associated with disrupted sensorimotor gating, such as with schizophrenia, could benefit from further evaluating strategies to modulate specifically cholinergic neurons in the medial septum.