Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic Reln deletion

Reelin is an essential extracellular matrix glycoprotein involved in the formation of cortical layers and has been associated with several neuropsychiatric conditions, such as schizophrenia (SCZ). To explore its role in brain function and its potential involvement in SCZ, we developed a Reln heterozygous deletion (Relndel/+) mouse model that mimics a genetic deletion observed in a Japanese patient with SCZ. In previous studies, we demonstrated that Relndel/+ mice exhibit cognitive impairments in a visual discrimination test. Here, we found that Relndel/+ mice displayed impairments in social novelty recognition, while social preference remained intact. Immunohistochemical analyses revealed a significant decrease in the numbers of calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic pyramidal neurons, gamma-aminobutyric acid (GABA)-ergic interneurons, and parvalbumin (PV)-positive interneurons in the medial prefrontal cortex (mPFC) of Relndel/+ mice. Furthermore, Relndel/+ mice exhibited significant deficits in excitatory spine density and morphology, as well as a decrease number of PV boutons in the mPFC compared to wild-type (WT) mice. Finally, we demonstrated that injection of AAV-R36-Myc virus into the mPFC can improve social novelty impairments in Relndel/+ mice, but no effects on WT control. These findings indicate that Relndel/+ mice could be a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Furthermore, our results with AAV-R36-Myc also suggest the therapeutic potential of Reelin replacement, warranting further investigation as a possible treatment strategy for SCZ.