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 that regulates cortical layers formation and has been implicated in several neuropsychiatric conditions, including 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 replicates a genetic deletion identified in a Japanese patient with SCZ. In previous studies, we demonstrated that Reln ^del/+ mice exhibit cognitive impairments in a visual discrimination test. In the present study, we found that Reln ^del/+ mice displayed impairments in social novelty recognition and social odor responses, whereas social preference and non-social odor responses remained intact. Immunohistochemical analyses revealed a significant decrease in the numbers of calcium/calmodulin-dependent protein kinase II-positive glutamatergic pyramidal neurons, gamma-aminobutyric acid-ergic interneurons, parvalbumin-positive interneurons and somatostatin-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, along with a reduced number of PV boutons in the mPFC compared to wild-type (WT) controls. Finally, we demonstrated that injection of adeno-associated virus (AAV)-R36-Myc into the mPFC improved social novelty impairments in Reln ^del/+ mice, with no observable effects in WT controls. These findings indicate that Reln ^del/+ mice provide a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Furthermore, the efficacy of AAV-R36-Myc highlights the therapeutic potential of Reelin replacement, warranting further investigation as a targeted treatment strategy for SCZ.