Glycine Transporter 1 Inhibitor, Bitopertin, Changes Excitatory and Inhibitory Network Connectivity in Mouse Medial...

Cognitive deficits in Schizophrenia (SCZ) are correlated with excitation-inhibition (E/I) imbalance within the medial prefrontal cortex (mPFC). E/I imbalance may arise from N-methyl-D-aspartate receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission. Previous research has shown that bitopertin, a glycine transporter 1 (GlyT1) inhibitor, restores E/I balance. We investigated how GlyT1 inhibition affects NMDAR-mediated signaling and reshapes connectivity between excitatory and inhibitory neurons in the mPFC. We examined the effect of bitopertin on NMDAR-mediated transmission between pyramidal neurons (PNs) and inhibitory interneurons (INs), including putative vasoactive intestinal peptide-expressing (VIP-like), putative somatostatin-expressing (SST-like), and parvalbumin-expressing (PV) INs in the mouse mPFC. Our study utilized several complimentary techniques including channelrhodopsin-assisted circuit mapping, two-photon ex vivo functional imaging, slice electrophysiological recordings, and network modeling. Bitopertin influenced NMDAR-mediated excitatory drive in an IN-subtype-specific manner, with a presynaptic independent mechanism. It had no effect on the EPSC input strength of VIP-like INs but decreased the input probability and area from which VIP-like INs received excitation. By contrast, Bitopertin strengthened excitatory synaptic connections to PV INs but had no effect on excitatory input area or probability. While increased excitation of inhibitory INs was expected to inhibit PN activity, the results showed no significant inhibition of PNs. This work uncovers the mode of action of bitopertin and the effects of GlyT1 inhibition on NMDA transmission within the mPFC network. Computational modeling suggests that these changes could contribute to partial normalization of network dynamics under simulated conditions of E/I imbalance mediated by NMDAR hypofunction. Together, we found that bitopertin chiefly impacts the inhibitory network, while minimally affecting PNs. This insight could aid the development of more effective therapies for cognitive dysfunctions caused by E/I imbalance.