SP4 Gene targeting for Schizophrenia phenotype rescue in mice

Abstract

Background: Schizophrenia is a complex psychiatric disorder affecting millions worldwide, with symptoms spanning cognitive deficits to hallucinations. Previous research has identified the SP4 gene as a significant risk factor for schizophrenia, associated with severe disruptions in neuronal function. Gene therapy presents a promising approach to addressing the genetic underpinnings of schizophrenia directly. This study aims to validate the SP4 gene as a drug target, as well as to explore the possibility to genetically rescue schizophrenic phenotypes. Methods: This study employed the adeno- associated virus (AAV) vector AAV-PHP.eB to deliver the eSYN-iCre construct across the entire brain in adult mice, leading to re-expression of the Sp4 gene. Schizophrenic phenotypes determined in previous studies were tested such as prepulse inhibition (PPI), response to ketamine and contextual memory. Results: The AAV-mediated gene therapy showed partial success in rescuing the PPI deficits in mice and significantly mitigated ketamine- induced hyperlocomotion in male mice, though results in female mice were complicated due to increase of locomotion caused by the Cre. Significant memory deficits were shown in not ameliorated by the treatment. Discussion & Conclusion: The study underscores the potential of the SP4 gene as a target for both gene therapy and small molecule drugs in treating schizophrenia. The successful delivery and expression of therapeutic genes across the brain demonstrate the viability of AAV vectors for CNS therapies, suggesting that gene therapy could offer a long-term remedy for psychiatric disorders. However, the gender-specific responses and partial rescue of phenotypes highlight the complexity of schizophrenia's genetic landscape and the need for further research into more targeted and comprehensive therapeutic approaches. This research opens avenues for the development of novel treatments that could profoundly impact the management and understanding of schizophrenia.