Input specific distal feed forward inhibition alteration in the mPFC of a mouse model important for the study of schizophrenia

PAFUNDO DE; PRETELL ANNAN, CA; FULGINITI, NM; BELFORTE, JE

CABA

Congreso; XXXVII SAN Annual Congress; 2022

Sociedad Argentina de Investigación en neurociencias

Schizophrenia is one of the most debilitating psychiatric disorders. While approximately 1% of human populationis aected by this disease, its causes are still unknown. The disease is characterized by positive, negativeand cognitive symptoms, being the latter highly debilitating and one important cause for disability inthe patients. The glutamate hypothesis of schizophrenia proposes that schizophrenia symptoms and importantlythe cognitive impairment are due to NMDA receptor (NMDAR) hypofunction. We have shown thatablation of NMDARs, exclusively in corticolimbic interneurons (preferentially in parvalbumin positive interneurons-PVin) and during early postnatal development in mice, results in a schizophrenia-like syndrome inadulthood. At the cortical circuit level the adult mice show hippocampal-prefrontal disconnection and prefrontalpyramidal neuron Excitation/Inhibition (E/I) imbalance.Inputs from distal regions to the prefrontal cortex such as the ventral hippocampus (vHip) are important forcognition, and decits in the vHip-prefrontal connection are found in patients. PVin function and connectivityare crucial for normal circuits function and their disfunction is associated with cognitive decits inschizophrenia. Furthermore, the reciprocal synapses between the fast spiking interneurons PVins (FSIs) andpyramidal neurons (PNs) can control local activity by feedback and feedforward inhibition (FFI). In the latter,inputs recruit PNs and interneurons and thus have important consequences for synaptic integration. Inputsfrom the vHip directly synapse both PNs and PVins in the mPFC, thus altered vHip-mPFC connectivity maydisrupt mPFC function in a complex manner. Knowing the relative synaptic strength to these neurons iscrucial to understand circuit disfunction in schizophrenia.Here we use a mouse model where the NMDA receptor is eliminated from corticolimbical interneuronsduring early postnatal development that shows functional and structural decits in the prefrontal circuitas well as a vHip-mPFC disconnection and behavioral impairments compatible with schizophrenia. Weexpressed channelrhodopsin in the CA1 region of the vHip using viral vectors and recorded the lightevoked EPSPs and EPSCs in PNs and FSIs of the homolateral mPFC. Alternatively, we performed similar experimentsexpressing channelrhodopsin in the contralateral (callosal) mPFC neurons. We found that therelative strength of vHP-mPFC inputs to PVins and PV is altered in the KOs reducing the eect of FFI in aspecic manner since the relative callosal mPFC-mPFC connections to PNs and PVins remain unaltered inthe KOs.