Partial rescue of schizophrenia-related phenotypes in young adult Sp4 hypomorphic mice.

In mice with reduced Sp4 expression, a gene linked to schizophrenia in humans, restoring Sp4 in young adults partially corrected two schizophrenia-related behavioral deficits—prepulse inhibition and hypersensitivity to ketamine—but did not improve context memory. The SP4 gene is strongly associated with schizophrenia risk; human studies show that loss of one copy increases odds of schizophrenia by about 9-fold. These results suggest that Sp4 restoration in adulthood may reverse some but not all behavioral abnormalities, supporting further investigation of SP4 as a potential drug target.

Study at a glance

Abstract

The Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) Consortium found that truncation of one copy of the SP4 gene has an odds ratio of 9.37 (3.38-29.7) for schizophrenia (SCZ). Human SP4 gene is also one of the 69 schizophrenia-risk genes prioritized by parallel genome-wide association studies (GWAS) and one of the two schizophrenia-risk genes shared between the SCHEMA and the GWAS, suggesting that more subtle common variants of the SP4 gene with a partial loss-of-function are likely involved in the pathogenesis of schizophrenia in the general population of patients. SP4 may also act as a hub of network in the regulation of many other schizophrenia-risk genes. Sp4 hypomorphic mice that have reduced Sp4 expression recapitulate several behavioral phenotypes related to schizophrenia such as deficient prepulse inhibition (PPI), hypersensitivity to ketamine in locomotion, and deficient context memory. We previously demonstrated cell-specific rescue of ketamine hypersensitivity by restoring Sp4 expression in forebrain GABAergic inhibitory neurons during embryogenesis. However, it is unknown whether restoration of Sp4 expression in young adult Sp4 hypomorphic mice may rescue these schizophrenia-related phenotypes when these phenotypes are still emerging. Such studies are critical for evaluation of SP4 as a potential target gene for schizophrenia drug development. Here, we use AAV.PHP.eB virus carrying Cre recombinase to restore Sp4 expression in the whole brains of young adult Sp4 hypomorphic mice. Our preliminary studies suggested that Sp4 partial restoration attenuated PPI deficits and ketamine locomotor hypersensitivity in adult male Sp4 hypomorphic mice but did not improve deficient context memory in Sp4 hypomorphic mice transduced with AAV/PHP.eB virus carrying the Cre gene. A large cohort of Sp4 hypomorphic mice is needed for the rescue experiments to validate our findings.