Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Abstract Pharmacological approaches to induce N-methyl-D-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in mice that underwent a 7-day subchronic phencyclidine (PCP 10mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus (HPC) to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds. Highlights Subchronic PCP treatment alters cognitive performance and evoked gamma synchronization in the prefrontal cortex. Subchronic PCP reduces number of parvalbumin-positive boutons and inhibitory synaptic transmission onto pyramidal neurons in layer 5/6 of the prelimbic cortex. Subchronic PCP reduces the strength of ventral hippocampal inputs to the medial prefrontal cortex. Frontostriatal circuits show robust dysconnectivity after subchronic PCP treatment. Abstract