1. Academic Validation
  2. DCC in the cerebral cortex is required for cognitive functions in mouse

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

  • Brain Pathol. 2024 Sep 18:e13306. doi: 10.1111/bpa.13306.
Yun-Qing Hu 1 Wei-Tang Liu 1 2 Yong Wu 3 Zhi-Bin Hu 1 Yun-Chao Tao 1 Qiong Zhang 4 Jia-Yin Chen 4 Ming Li 5 Ling Hu 4 Yu-Qiang Ding 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
  • 2 Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
  • 3 Research Center for Mental Health and Neuroscience, Wuhan Mental Health Center, Jianghan University, Wuhan, China.
  • 4 Department of Laboratory Animal Science, Fudan University, Shanghai, China.
  • 5 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Abstract

Schizophrenia (SZ) is a highly heritable mental disorder, and genome-wide association studies have identified the association between deleted in colorectal Cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p-AKT and p-GSK3α/β were decreased, which was responsible for impaired PPI in the DCC-deficient mice. Finally, the DCC-deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta-oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ-related risky gene and when defective, may promote SZ-like pathogenesis and behavioral phenotypes in mice.

Keywords

DCC; GWAS; cerebral cortex; schizophrenia; sensorigating.

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