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

Abstract 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 ( Reln del/+ ) mouse model that mimics a genetic deletion observed in a Japanese patient with SCZ. In previous studies, we demonstrated that Reln del/+ mice exhibit cognitive impairments in a visual discrimination test. Here, we found that Reln del/+ 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 Reln del/+ mice. Furthermore, Reln del/+ 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 Reln del/+ mice, but no effects on WT control. These findings indicate that Reln del/+ mice could be a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Futhermore, our results with AAV-R36-Myc also suggest the therapeutic potential of Reelin replacement, warranting further investigation as a possible treatment strategy for SCZ. Highlights Reelin deficiency disrupts social novelty, but not social preference, in Reln del/+ mice Reln del/+ mice serve as a novel model to investigate impairments of neuronal mechanisms on schizophrenia AAV-R36-myc injection rescues social novelty deficits in Reln del/+ mice Reelin replacement therapy is a potential treatment for schizophrenia Graphical abstract