IMPACT ON TRANSCALLOSAL, LONG RANGE AND LOCAL MPFC EXCITATORY INPUTS BY EARLY POSTNATAL NMDA RECEPTOR ABLATION

Alterations of prefrontal cortex (PFC) microcircuit are considered pathophysiologically fundamental in schizophrenia. Excitatory pyramidal neurons (PNs) present reduced dendritic spine density and excitatory synapses, while inhibitory GABAergic interneurons (INs) show diminished levels of GAD67 and parvalbumin. Normal cortical circuit wiring relies on proper postnatal maturation of INs, with an increase in inhibition during adolescence establishing an adult excitation/inhibition (E/I) balance. Alterations in this process could lead to an E/I imbalance, possibly related to the neurodevelopmental aspect of schizophrenia. We have shown that mice with an early postnatal NMDA receptor ablation in corticolimbic INs—primarily parvalbumin-positive—present adult-emerging schizophrenia-like phenotypes, a ventral hippocampus (vHip)-mPFC disconnection and a functional mPFC E/I imbalance revealed only by increased cortical processing. Here, we further evaluated the functional and structural E/I balance within the mPFC. We injected an AAV-ChR2-YFP into either the contralateral mPFC or ipsilateral vHip and a blood-brain barrier–crossing AAV-PHP.eB-TdTomato for sparse labelling of PNs. We assessed long-range vHip–mPFC, transcallosal mPFC–mPFC, and local mPFC excitatory projections, electrophysiologically and by immunofluorescence. Hereby, we found a greater excitatory drive from mPFC–mPFC projections onto fast-spiking INs than onto PNs, regardless of genotype. However, long-range vHip–mPFC inputs failed to show this pattern in knockouts, resulting in impaired feed-forward inhibition evoked by vHip–mPFC, but not mPFC–mPFC, projections. Preliminary results further suggest a source-dependent structural E/I imbalance. Thus, early postnatal NMDA receptor ablation from INs impacts on the development of mPFC microcircuits, differentially affecting inputs from diverse sources critical for normal mPFC functioning.