DCC in the cerebral cortex is required for cognitive functions in mouse.

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Schizophrenia (SZ) is highly heritable, with genetic links to the deleted in colorectal cancer (DCC) gene.
• Previous research indicated reduced DCC expression in the brains of SZ patients.

Purpose of the Study:

• To investigate the role of DCC in SZ pathogenesis.
• To identify novel DCC single nucleotide polymorphisms (SNPs) associated with SZ.
• To explore the behavioral and molecular consequences of DCC deficiency in mice.

Main Methods:

• Generated DCC conditional knockout (CKO) mice with targeted deletion in cortical layers V and VI.
• Assessed behavioral phenotypes including fear memory, spatial memory, and sensorimotor gating (prepulse inhibition test).
• Analyzed molecular changes, including protein levels (p-AKT, p-GSK3α/β), neuronal spine density, and brain oscillations.

Main Results:

• DCC deletion in cortical layer VI, but not layer V, impaired fear/spatial memory and sensorimotor gating.
• Olanzapine treatment restored sensorimotor gating in DCC-deficient mice.
• Reduced p-AKT and p-GSK3α/β levels, decreased pyramidal neuron spine density, and disturbed delta-oscillations were observed in DCC-deficient mice.

Conclusions:

• DCC is a risk gene for schizophrenia, and its deficiency can promote SZ-like phenotypes.
• Downstream signaling pathways involving AKT and GSK3α/β are implicated in DCC-related SZ pathogenesis.
• These findings provide novel insights into the molecular mechanisms underlying schizophrenia.