CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• GABAergic dysfunction is linked to schizophrenia, particularly cognitive impairments.
• The GAD1 gene, encoding the GABA synthetic enzyme GAD67, is downregulated in schizophrenia patients.
• Previous Gad1 knockout mice studies were limited by perinatal lethality.

Purpose of the Study:

• To investigate the role of GAD1 loss of function in schizophrenia-related symptoms.
• To establish a viable Gad1 knockout rat model for studying schizophrenia.

Main Methods:

• CRISPR/Cas9 genome editing was used to generate Gad1 knockout rats.
• Characterization included biochemical analysis of GABA levels and behavioral testing in adult rats.

Main Results:

• Gad1 knockout rats showed reduced brain GABA levels (~52%) and survived to adulthood (33%).
• These rats exhibited spatial memory impairments and altered behaviors, including NMDA receptor antagonist sensitivity and social interaction changes.
• Adult neurogenesis in the hippocampus remained unaffected.

Conclusions:

• Gad1 knockout rats provide a valuable model for schizophrenia, encompassing cognitive deficits and behavioral alterations.
• This study highlights the importance of considering species-specific differences in developing animal models for human diseases.