Deletion of Tet1 in Mice with Impaired Prefrontal Cortex Functions by Activating the NGF/TrkA Signaling Pathway

Abstract

Abstract Tet1 (ten-eleven translocation methylcytosine dioxygenase 1) is the enzyme methylcytosine dioxygenase of DNA demethylation in the nervous system. Tet1 controls and mediates gene transcription, memory formation, and extinction. However, little is known about Tet1 in prefrontal cortex (PFC) functions especially in the medial prefrontal cortex (mPFC), which controls cortex flexibility and emotional reactivity in the CNS. This study conducted behavioral tests including an open field test, sociability and social novelty preference tests, social dominance, and prepulse inhibition test to examine brain functions, especially PFC functions after the deletion of Tet1. The mPFC from Tet1 KO mice and WT adult mice was analyzed using qRT-PCR to assess neuron growth-related genes, including Gsk3β, Pi3k, Crx4, Fgfr1, Fgfr2, Egfr, Dbn1, Akt2, Vegf, Vegfr, and Akt3. Subsequently, primary PFC neuronal cells were administered shTet1 to knockdown the Tet1 gene and function. We found that the deletion of Tet1 in the mouse brains impaired social interaction, novelty, and prepulse inhibition (PPI) in the mice. Knockdown of the Tet1 gene influenced the growth and complexity of neurons. The increase in Ngf and Bdnf by Western blotting were found in Tet1 deficient mice. The results support and complement the view that Tet1 deficiency may be related to schizophrenia.